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1.  Hemolytic disease of the fetus and newborn caused by anti-D and anti-S alloantibodies: a case report 
Introduction
Hemolytic disease of the fetus and newborn is most commonly caused by anti-D alloantibody. It is usually seen in Rhesus D (RhD)-negative mothers that have been previously sensitized. We report here a case of hemolytic disease of the fetus and newborn in a newborn baby caused by anti-D and anti-S alloantibodies, born to a mother who was RhD negative, but with no previous serological evidence of RhD alloimmunization.
Case presentation
A one-day-old Chinese baby boy was born to a mother who was group A RhD negative. The baby was jaundiced with hyperbilirubinemia, but with no evidence of infection. His blood group was group A RhD positive, his direct Coombs' test result was positive and red cell elution studies demonstrated the presence of anti-D and anti-S alloantibodies. Investigations performed on the maternal blood during the 22 weeks of gestation showed the presence of anti-S antibodies only. Repeat investigations performed post-natally showed the presence of similar antibodies as in the newborn and an anti-D titer of 1:32 (0.25 IU/mL), which was significant. A diagnosis of hemolytic disease of the fetus and newborn secondary to anti-D and anti-S was made. The baby was treated with phototherapy and close monitoring. He was discharged well after five days of phototherapy.
Conclusions
This case illustrates the possibility of an anamnestic response of allo-anti-D from previous sensitization in a RhD-negative mother, or the development of anti-D in mid-trimester. Thus, it highlights the importance of thorough antenatal ABO, RhD blood grouping and antibody screening, and if necessary, antibody identification and regular monitoring of antibody screening and antibody levels for prevention or early detection of hemolytic disease of the fetus and newborn, especially in cases of mothers with clinically significant red cell alloantibody.
doi:10.1186/1752-1947-6-71
PMCID: PMC3299637  PMID: 22348809
2.  Hemolytic disease of fetus and newborn due to maternal red blood cell alloantibodies in the Malay population 
Background:
Maternal red blood cell (RBC) alloimmunization may lead to production of harmful antibodies that result in hemolytic disease of fetus and newborn (HDFN). There is insufficient data on the prevalence of HDFN due to RBC alloantibodies in the Malay neonatal population.
Aim:
The aim of this study was to determine the incidence of HDFN in the Malay neonatal population due to clinically significant RBC alloantibodies.
Subjects and Methods:
A cross sectional study was conducted in Transfusion Medicine Unit, Hospital Universitiy Sains Malaysia over one year period from January to December 2009. A total of 5163 Malay pregnant women who attended labor room for delivery were collected and analyzed prospectively. The blood samples were subjected to the standard immunohematological procedure for RBC antibody screening and identification using reagents of Diamed-ID Gel microtyping system. All the newborns with RBC alloantibody were investigated for the evidence of HDFN.
Results:
Thirty (0.58%) women were found to have clinically significant RBC alloantibodies. Most of the alloantibodies belonged to Rhesus (Rh) system (56.7%) where anti-E (33.3%) was the most common followed by anti-D (10.0%). Rh antibodies were the main cause of HDFN in fourteen (0.27%) neonates. Anti-D and anti-c were identified to cause moderate to very severe HDFN.
Conclusions:
With the low prevalence of clinically significant RBC alloantibodies and HDFN, routine antenatal antibody screening practice may not be advised as a routine practice at present, preferably reserved for those women of RhD negative or with history of HDFN, significantly of those attributed to anti-c.
doi:10.4103/0973-6247.137449
PMCID: PMC4140053  PMID: 25161351
Clinically significant alloantibodies; HDFN; Malay
3.  Hemolytic disease of the fetus and newborn: Current trends and perspectives 
The spectrum of hemolytic disease of the newborn has changed over the last few decades. With the implementation of Rhesus D immunoprophylaxis, hemolytic disease due to ABO incompatibility and other alloantibodies has now emerged as major causes of this condition. Though in developing countries, anti D is still a common antibody in pregnant women, many Asian countries have identified alloantibodies other than anti D as a cause of moderate-severe hemolytic disease. The most concerned fact is that, some of these have been described in Rh D positive women. It appears that universal antenatal screening in all pregnant women needs to be initiated, since Rh D positive women are just as likely as D negative women to form alloantibodies. Many developed nations have national screening programs for pregnant women. This is necessary to ensure timely availability of antigen negative blood and reduce effects on the newborn. Although universal screening seems justified, the cost and infrastructure required would be immense. Developing countries and under resourced nations need to consider universal antenatal screening and frame guidelines accordingly.
doi:10.4103/0973-6247.75963
PMCID: PMC3082712  PMID: 21572705
Newborn hemolytic disease; red cell alloimmunisation; antenatal antibody screening
4.  Prevalence, specificity and risk of red blood cell alloantibodies among hospitalised Hubei Han Chinese patients 
Blood Transfusion  2014;12(1):56-60.
Background
The prevalence, specificity and risk of red blood cell alloantibodies vary widely among different geographic areas, races, and diseases and according to different methods of study, but no data are available on the Chinese Han population, who were investigated in the present study.
Materials and methods
Antibody screening was conducted among 42,517 hospitalised Hubei Han Chinese individuals using column agglutination technology. Samples that were positive in antibody screening were subjected to antibody identification by the tube test. Clinical data, including gender, age, race, transfusion history and records of alloantibody detection, transfusion reactions or haemolytic disease of the newborn, were collected to analyse the prevalence and specificity of alloantibodies and complications associated with them.
Results
A total of 212 patients with alloantibodies were identified among 42,517 patients, yielding a prevalence of 0.50% in this study. Significantly different prevalence rates were observed according to age and sex. The most frequently identified alloantibodies were anti-E (87/212, 41.0%), anti-D (45/212, 21.2%), anti-M (41/212, 19.3%) and a combination of anti-E and anti-c (13/212, 6.1%). Haemolytic disease was observed in 13 infants with anti-D, three infants with anti-E and one infant with anti-Fya alloantibodies. Delayed haemolytic transfusion reactions occurred in four patients with alloantibodies.
Discussion
In hospitalised Hubei Han Chinese individuals, the overall prevalence of alloantibodies was 0.50%, with anti-E, anti-D and anti-M being the most frequently identified alloantibodies. These results indicate that anti-D and anti-E alloantibodies were major risk factors for haemolytic disease of the newborn or delayed haemolytic transfusion reactions in this study population.
doi:10.2450/2013.0013-13
PMCID: PMC3926729  PMID: 24333071
RBC alloantibodies; antibody prevalence; antibody specificity; Han Chinese
5.  Frequencies of maternal red blood cell alloantibodies in Port Harcourt, Nigeria 
Background:
Alloantibodies of clinical importance can cause transfusion reactions or hemolytic disease of the fetus and newborn (HDFN). The frequencies of these antibodies have not been reported in our locality.
Aims:
To determine the frequency of occurrence of alloantibodies among pregnant women in Port Harcourt, Nigeria.
Settings and Design:
This is a prospective study, which was carried out in the Braithwaite Memorial Specialist Hospital, Port Harcourt, Nigeria.
Materials and Methods:
Screening and identification of red blood cell alloantibodies was done on the sera of 500 pregnant women using the DiaMed, DiaCell, and DiaPanel reagents (Cressier, Switzerland). ABO and Rh blood groups were done using antisera bought from Biotec (Ipswich, UK).
Results:
Alloantibodies were identified in the serum of 17 of the 500 (3.4%) pregnant women. The specificity of the antibodies was as follows: anti-C 6 (1.2%), anti-E 3 (0.6%), anti-Jsb 3 (0.6%), and anti-K 5 (1.0%). No anti-D was identified despite 8.6% of the study population being Rhesus D (Rh D) negative. The distribution of the antibodies was found to be independent of the blood groups of the participants (χ2 = 4.050, P = 0.670). Blood group O constituted the highest percentage (48.0%).
Conclusion:
This study has identified the presence of non-Rh D antibodies to the proportion of 3.4%. Rh D antibody was absent in this population irrespective of the relatively high percentage of Rh D negative women. There is a need to determine the actual risk these antibodies may pose to the antenatal women and to include antibody screening and identification in routine antenatal care.
doi:10.4103/0973-6247.75987
PMCID: PMC3082715  PMID: 21572714
Alloantibodies; frequencies; non-Rh D antibodies; HDFN; Nigeria
6.  Occurrence of ABO And RhD Incompatibility with Rh Negative Mothers 
Materia Socio-Medica  2013;25(4):255-258.
Introduction:
Hemolytic disease of the newborn was first described in the medical literature 1609, when it was diagnosed in one French housewife. In 1932 Diamond and colleagues described the mutual relationship of fetal hydrops, jaundice, anemia and erythoblastosis, which was later called fetal erytroblastosis. Hemolytic disease of the newborn (HDN) in the strict sense is considered disease whose basis is accelerated immune destruction of fetal/child erythrocytes that are bound to IgG antibodies of maternal origin. These antibodies are directed against antigens of father’s origin, which are present in the fetal/children’s erythrocytes and that the mother’s immune system recognizes them as foreign antigens.
Goal:
The goal is that in the period from January 1st 2011 to October 23st 2013 determine the frequency of ABO and Rh D incompatibilities in our sample of pregnant women/mothers, and to underscore the importance of regular check of ABO Rh D negative pregnant women and application specific Rh D protection.
Material and methods:
In the General Hospital “Prim. Dr. Abdulah Nakas” in Sarajevo by retrospective study are followed several relevant variables. Immune alloantibodies were detected in vivo by indirect Coombs test (ICT) with serum mother and O test erythrocytes, by direct Coombs test (DCT) with erythrocytes of a newborn.
Results:
The total number of births ABO Rh D negative was 596 (14%) and ABO Rh D positive mothers 4261 (86%). Of the total number of Rh D negative mothers there was A Rh D: negative mothers 42%; O Rh D negative 33%; B Rh D: negative 17% and AB Rh D: negative 8%. Most of immune antibodies appear in mothers with O Rh D: negative blood type. The emergence of immune antibodies in the Rh D negative mothers was 1%, the appearance of ABO incompatibilities amounted to 2.3% of our sample.
Conclusion:
In order to reduce the occurrence of alloimmunization of the mother to erythrocyte antigens of the newborn that can lead to major complications in subsequent pregnancies of Rh D: negative mothers and HDN constant monitoring in order to prevent them is necessary. Prevention is essential because once immunized mother will remain immunized for life.
doi:10.5455/msm.2013.25.255-258
PMCID: PMC3914752  PMID: 24511269
ABO and RhD incompatibility; Rh negative mothers; incidence; Bosnia and Herzegovina.
7.  The First Korean Case Report of Anti-Gerbich 
Annals of Laboratory Medicine  2012;32(6):442-444.
In this study, we report the first Korean case of an anti-Gerbich (Ge) alloantibody to a high-incidence antigen that belongs to the Ge blood group system. The alloantibody was detected in a middle-aged Korean woman who did not have a history of transfusion. Her blood type was B+, and findings from the antibody screening test revealed 1+ reactivity in all panels except the autocontrol. The cross-matching test showed incompatible results with all 5 packed red blood cells. Additional blood type antigen and antibody tests confirmed the anti-Ge alloantibody. While rare, cases of hemolytic transfusion reaction or hemolytic disease in newborns due to anti-Ge have been recently reported in the literature. Therefore, additional further studies on alloantibodies to high-incidence antigens, including anti-Ge, are necessary in the future.
doi:10.3343/alm.2012.32.6.442
PMCID: PMC3486941  PMID: 23130346
Ge; Blood group antigens; Transfusion
8.  Risk of Early-Onset Neonatal Infection with Maternal Infection or Colonization: A Global Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(8):e1001502.
Grace Chan and coauthors conducted a systematic review and meta-analysis of studies evaluating the risk of neonatal infection or colonization during the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.
Please see later in the article for the Editors' Summary
Background
Neonatal infections cause a significant proportion of deaths in the first week of life, yet little is known about risk factors and pathways of transmission for early-onset neonatal sepsis globally. We aimed to estimate the risk of neonatal infection (excluding sexually transmitted diseases [STDs] or congenital infections) in the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.
Methods and Findings
We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, and the World Health Organization Regional Databases for studies of maternal infection, vertical transmission, and neonatal infection published from January 1, 1960 to March 30, 2013. Studies were included that reported effect measures on the risk of neonatal infection among newborns exposed to maternal infection. Random effects meta-analyses were used to pool data and calculate the odds ratio estimates of risk of infection. Eighty-three studies met the inclusion criteria. Seven studies (8.4%) were from high neonatal mortality settings. Considerable heterogeneity existed between studies given the various definitions of laboratory-confirmed and clinical signs of infection, as well as for colonization and risk factors. The odds ratio for neonatal lab-confirmed infection among newborns of mothers with lab-confirmed infection was 6.6 (95% CI 3.9–11.2). Newborns of mothers with colonization had a 9.4 (95% CI 3.1–28.5) times higher odds of lab-confirmed infection than newborns of non-colonized mothers. Newborns of mothers with risk factors for infection (defined as prelabour rupture of membranes [PROM], preterm <37 weeks PROM, and prolonged ROM) had a 2.3 (95% CI 1.0–5.4) times higher odds of infection than newborns of mothers without risk factors.
Conclusions
Neonatal infection in the first week of life is associated with maternal infection and colonization. High-quality studies, particularly from settings with high neonatal mortality, are needed to determine whether targeting treatment of maternal infections or colonization, and/or prophylactic antibiotic treatment of newborns of high risk mothers, may prevent a significant proportion of early-onset neonatal sepsis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Millennium Development Goal 4 (MDG4)—one of eight goals agreed by world leaders in 2000 to eradicate extreme poverty globally—aims to reduce under-five mortality (deaths) to one-third of its 1990 level (12 million deaths). Progress towards reducing child mortality has accelerated recently, but MDG4 is unlikely to be met, partly because of slow progress towards reducing neonatal mortality—deaths during the first 28 days of life. Neonatal deaths now account for a greater proportion of global child deaths than in 1990. Nearly half of the children who die before their fifth birthday die during the neonatal period, with babies born in low-middle-income countries in sub-Saharan Africa and southern Asia being at the highest risk of neonatal death. Bacterial infections such as infections of the bloodstream (bacteremia/sepsis), lungs (pneumonia), and the brain's protective covering (meningitis) are responsible for a quarter of neonatal deaths. Newborns can acquire infections during birth by picking up bacteria (in particular Group B streptococcus or GBS) that are present in their mother's reproductive tract and that may or may not cause disease in the mother. Bacteria colonizing the maternal perineum (the area between the anus and the vagina) can move up the vaginal canal into the amniotic sac (the fluid-filled bag in which the baby develops). Maternal bacteremia is another source of bacterial transmission from mother to fetus. Other risk factors for neonatal infection include pre-labor rupture of the membranes (PROM) of the amniotic sac, preterm PROM, and prolonged rupture of membranes.
Why Was This Study Done?
In high-income settings, prophylactic (preventative) antibiotic treatment during labor (based on microbiological screening or risk factors such as PROM) and early diagnosis and treatment of sepsis in newborn babies has greatly reduced deaths from early-onset neonatal bacterial infection. Yet, relatively little is known about the risk factors and transmission pathways for this condition globally. In this global systematic review and meta-analysis, the researchers estimate the risk of neonatal bacterial infections (excluding sexually transmitted diseases) among newborns of mothers with bacterial infection or colonization around the time of birth. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies (only seven of which were undertaken in settings with high neonatal mortality) that included data on laboratory-confirmed maternal infection, maternal infection indicated by clinical signs and symptoms, maternal colonization (positive bacterial cultures from the reproductive tract without any signs or symptoms of infection), or risk factors for infection such as PROM and data on neonatal infection (laboratory-confirmed or clinically indicated) or colonization. Because different studies used different definitions for infection and colonization, the researchers pooled the data from subsets of the studies using random effects meta-analysis, which allows for heterogeneity (inconsistencies) between studies. Newborns of mothers with laboratory-confirmed infection had a 6.6-fold higher risk of laboratory-confirmed infection than newborns born to mothers without laboratory-confirmed infection. Newborns of mothers with bacterial colonization had a 9.4-fold higher risk of laboratory-confirmed infection than newborns of non-colonized mothers. Finally, compared to newborns of mothers without risk factors for infection, newborns of mothers with PROM or other risk factors had a 2.3-fold higher risk of infection.
What Do These Findings Mean?
These findings indicate that an increased risk of early-onset neonatal infection is associated with maternal infection and maternal colonization and provide some quantification of the excess risk. Because all the studies were facility-based and mostly from urban settings in high-income countries, these findings provide no information about the risk of neonatal infection among home births, rural births or births at community facilities in low-income countries, which limits their generalizability. Other aspects of the studies included in this systematic review and meta-analysis are also likely to limit the accuracy of the findings. Nevertheless, these findings suggest that better diagnosis and treatment of maternal infections and colonization in low- to middle-income countries where neonatal mortality is high might substantially reduce the incidence of neonatal infections and that the development of a simple algorithm that combines clinical signs and risk factors to diagnose maternal infections might be useful in regions where laboratory facilities are unavailable. Moreover, they highlight the need for more studies of maternal and neonatal infection and colonization in resource-poor settings with high neonatal mortality.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001502.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about neonatal survival and health; its Committing to Child Survival: a Promise Renewed webpage includes links to its 2012 progress report and to a video about how new health centers are helping India battle high neonatal death rates
The World Health Organization has information about Millennium Development Goal 4 and about newborn health (some information in several languages)
Countdown to 2015 provides additional information on maternal, newborn, and child survival, including its 2012 report Building a Future for Women and Children
Kidshealth, a resource provided by the not-for-profit Nemours Foundation, has information on neonatal infections for parents (in English and Spanish)
The MedlinePlus Encyclopedia has a page on neonatal sepsis (in English and Spanish)
A personal story about fatal neonatal bacterial meningitis is available on the website of Meningitis UK, a not-for profit organization; the site also includes a survivor story
doi:10.1371/journal.pmed.1001502
PMCID: PMC3747995  PMID: 23976885
9.  Hemolytic disease of the fetus and newborn caused by anti-E 
Objective:
Maternal allo-antibody production is stimulated when fetal red blood cells are positive for an antigen absent on the mother's red cells. The maternal IgG antibodies produced will pass through the placenta and attack fetal red cells carrying the corresponding antigen. Allo-immune hemolytic disease of the fetus and newborn caused by anti-E rarely occurs.
Case summary:
We report two cases of anti-E hemolytic diseases in neonates. One of the neonates had severe hemolysis presenting with severe anemia, thrombocytopenia, and conjugated hyperbilirubinemia, while the other had moderate anemia and unconjugated hyperbilrubinemia. Although both the neonates were treated by phototherapy and intravenous immunoglobulin, one of them received double volume exchange transfusion.
Conclusion:
There appeared to be an increase in the occurrence of hemolytic disease of the fetus and newborn caused by Rh antibodies other than anti-D. In this case report, both patients presented with anemia and hyperbilirubinemia but were successfully treated, with a favorable outcome.
doi:10.4103/0973-6247.106750
PMCID: PMC3613674  PMID: 23559775
Allo-antibody; anti-E; hemolytic disease of the fetus and newborn
10.  Transfusion of murine RBCs expressing the human KEL glycoprotein induces clinically significant alloantibodies 
Transfusion  2013;54(1):179-189.
Background
Red blood cell (RBC) alloantibodies to non-self antigens may develop following transfusion or pregnancy, leading to morbidity and mortality in the form of hemolytic transfusion reactions or hemolytic disease of the newborn. A better understanding of the mechanisms of RBC alloantibody induction, or strategies to mitigate the consequences of such antibodies, may ultimately improve transfusion safety. However, such studies are inherently difficult in humans.
Study Design and Methods
We recently generated transgenic mice with RBC specific expression of the human KEL glycoprotein, with the KEL2 or KEL1 antigens. Herein, we investigate recipient alloimmune responses to transfused RBCs in this system.
Results
Transfusion of RBCs from KEL2 donors into wild type recipients (lacking the human KEL protein but expressing the murine KEL orthologue) resulted in dose dependent anti-KEL glycoprotein IgM and IgG antibody responses, enhanced by recipient inflammation with poly (I:C). Boostable responses were evident upon repeat transfusion, with morbid appearing alloimmunized recipients experiencing rapid clearance of transfused KEL2 but not control RBCs. Although KEL1 RBCs were also immunogenic following transfusion into wild type recipients, transfusion of KEL1 RBCs into KEL2 recipients or vice versa failed to lead to detectable anti-KEL1 or anti-KEL2 responses.
Conclusions
This murine model, with reproducible and clinically significant KEL glycoprotein alloantibody responses, provides a platform for future mechanistic studies of RBC alloantibody induction and consequences. Long term translational goals of these studies include improving transfusion safety for at risk patients.
doi:10.1111/trf.12217
PMCID: PMC3732531  PMID: 23621760
11.  Alloimmunization screening after transfusion of red blood cells in a prospective study 
Background
Several irregular red blood cell alloantibodies, produced by alloimmunization of antigens in transfusions or pregnancies, have clinical importance because they cause hemolysis in the fetus and newborn and in transfused patients.
Objective
a prospective analysis of patients treated by the surgical and clinical emergency services of Hospital de Clínicas of the Universidade Federal do Triângulo Mineiro (HC/UFTM), Brazil was performed to correlate alloimmunization to clinical and epidemiological data.
Methods
Blood samples of 143 patients with initial negative antibody screening were collected at intervals for up to 15 months after the transfusion of packed red blood cells. Samples were submitted to irregular antibody testing and, when positive, to the identification and serial titration of alloantibodies. The Fisher Exact test and Odds Ratio were employed to compare proportions.
Results
Fifteen (10.49%) patients produced antibodies within six months of transfusion. However, for 60% of these individuals, the titers decreased and disappeared by 15 months after transfusion. Anti-K antibodies and alloantibodies against antigens of the Rh system were the most common; the highest titer was 1:32 (anti-K). There was an evident correlation with the number of transfusions.
Conclusions
Given the high incidence of clinically important red blood cell alloantibodies in patients transfused in surgical and clinical emergency services, we suggest that phenotyping and pre-transfusion compatibilization for C, c, E, e (Rh system) and K (Kell system) antigens should be extended to all patients with programmed surgeries or acute clinical events that do not need emergency transfusions.
doi:10.5581/1516-8484.20120051
PMCID: PMC3459635  PMID: 23049421
Blood transfusion; Blood group antigens; Hemolysis; Immunophenotyping; Emergencies
12.  The prevalence of irregular erythrocyte antibodies among antenatal women in Delhi 
Blood Transfusion  2011;9(4):388-393.
Background
Universal screening of all antenatal women, including D antigen-positive pregnant ones, is mandatory in most developed countries. However, no guidelines on this issue are available for developing countries such as India. Furthermore, there is limited information on immunisation rates in pregnant women (D antigen-positive and D antigen-negative) from India. We, therefore, studied the prevalence of alloantibodies among multigravida women in India.
Materials and methods
In this prospective study, carried out to detect the prevalence of alloantibodies among multigravida women in India, 3,577 multigravida women attending antenatal clinics were typed for ABO and D antigens and screened for alloantibodies by column agglutination technology. The medical history and detailed obstetric history of these women were reviewed and information recorded on any prior haemolytic disease of the foetus and newborn among siblings and/or blood transfusions.
Results
The overall prevalence of alloantibodies in this study was 1.25%. There was a statistically significant difference between alloimmunisation rates in the D antigen-negative and D antigen-positive groups (10.7% versus 0.12%, respectively). Anti-D antibody contributed to 78.4% of total alloimmunisations in our study.
Discussion
Anti-D was the most common culprit responsible for alloimmunisation. Other alloantibodies found included anti-C, anti-M, anti-S and anti-c. Large-scale population-based studies are required to assess the real magnitude of alloimmunisation in pregnant women in India.
doi:10.2450/2011.0050-10
PMCID: PMC3200407  PMID: 21839025
alloimmunisation; irregular erythrocyte antibodies; pregnancy
13.  Rh isoimmunization in Sub-Saharan Africa indicates need for universal access to anti-RhD immunoglobulin and effective management of D-negative pregnancies 
Transplacental or fetomaternal hemorrhage (FMH) may occur during pregnancy or at delivery and lead to immunization to the D antigen if the mother is Rh-negative and the baby is Rh-positive. This can result in hemolytic disease of the fetus and newborn (HDFN) in subsequent D-positive pregnancies. The aim of this study is to highlight the challenges associated with the effective management and prevention of Rh alloimmunization among Rh-negative women in Sub-Saharan Africa. In most Sub-Saharan African countries, there is poor and sometimes no alloimmunization prevention following potentially sensitizing events and during medical termination of pregnancy in Rh-negative women. Information about previous pregnancies and termination are often lacking in patients’ medical notes due to poor data management. These issues have made the management of Rh-negative pregnancy a huge challenge. Despite the fact that the prevalence of Rh-negative phenotype is significantly lower among Africans than Caucasians, Rh alloimmunization remains a major factor responsible for perinatal morbidity in Sub-Saharan Africa and may result in the compromise of the woman’s obstetric care due to the unaffordability of anti-D immunoglobulin. There is the urgent need for the implementation of universal access to anti-D immunoglobulin for the Rh-negative pregnant population in Africa. Anti-D immunoglobulin should be available in cases of potentially sensitizing events such as amniocentesis, cordocentesis, antepartum hemorrhage, vaginal bleeding during pregnancy, external cephalic version, abdominal trauma, intrauterine death and stillbirth, in utero therapeutic interventions, miscarriage, and therapeutic termination of pregnancy. There is also the need for the availability of FMH measurements following potentially sensitizing events. The low-cost acid elution method, a modification of the Kleihauer–Betke (KB) test, can become a readily available, affordable, and minimum alternative to flow cytometric measurement of FMH. Knowledge of anti-D prophylaxis among obstetricians, biomedical scientist, midwives, traditional birth attendants, pharmacists, and nurses in Africa needs to be improved. This will facilitate quality antenatal and postnatal care offered to Rh-negative pregnant population and improve perinatal outcomes.
doi:10.2147/IJWH.S15165
PMCID: PMC3024894  PMID: 21270966
rhesus isoimmunization; Sub-Saharan Africa; universal access; anti-D; management; Rh-negative women
14.  Responder Individuality in Red Blood Cell Alloimmunization 
Summary
Many different factors influence the propensity of transfusion recipients and pregnant women to form red blood cell alloantibodies (RBCA). RBCA may cause hemolytic transfusion reactions, hemolytic disease of the fetus and newborn and may be a complication in transplantation medicine. Antigenic differences between responder and foreign erythrocytes may lead to such an immune answer, in part with suspected specific HLA class II associations. Biochemical and conformational characteristics of red blood cell (RBC) antigens, their dose (number of transfusions and pregnancies, absolute number of antigens per RBC) and the mode of exposure impact on RBCA rates. In addition, individual circumstances determine the risk to form RBCA. Responder individuality in terms of age, sex, severity of underlying disease, disease- or therapy-induced immunosuppression and inflammation are discussed with respect to influencing RBC alloimmunization. For particular high-risk patients, extended phenotype matching of transfusion and recipient efficiently decreases RBCA induction and associated clinical risks.
doi:10.1159/000369179
PMCID: PMC4280446
Alloimmunization; Red blood cell antibodies; Red blood cell antigens
15.  Hemolytic Disease of the Newborn Due to Anti-c Isoimmunization: A Case Report 
The Rhesus (Rh) blood group is one of the most complex blood groups known in humans. It has remained of primary importance in obstetrics, being the main cause of hemolytic disease of the newborn (HDN). Anti-D causes the most severe form of HDN. Other Rh allo antibodies that are capable of causing severe HDN include anti-c, which clinically is the most important Rh antigen after the D antigen. We report a case of hemolytic disease of the newborn due to Rh anti-c in an infant of an Rh positive mother.
doi:10.1007/s12288-012-0159-6
PMCID: PMC3710558  PMID: 24426362
Hemolytic disease; New born; Anti-c
16.  Evolutionary genetics of the human Rh blood group system 
Human genetics  2012;131(7):1205-1216.
The evolutionary history of variation in the human Rh blood group system, determined by variants in the RHD and RHCE genes, has long been an unresolved puzzle in human genetics. Prior to medical treatments and interventions developed in the last century, the D-positive children of D-negative women were at risk for hemolytic disease of the newborn, if the mother produced anti-D antibodies following sensitization to the blood of a previous D-positive child. Given the deleterious fitness consequences of this disease, the appreciable frequencies in European populations of the responsible RHD gene deletion variant (for example, 0.43 in our study) seem surprising. In this study, we used new molecular and genomic data generated from four HapMap population samples to test the idea that positive selection for an as-of-yet unknown fitness benefit of the RHD deletion may have offset the otherwise negative fitness effects of hemolytic disease of the newborn. We found no evidence that positive natural selection affected the frequency of the RHD deletion. Thus, the initial rise to intermediate frequency of the RHD deletion in European populations may simply be explained by genetic drift/ founder effect, or by an older or more complex sweep that we are insufficiently powered to detect. However, our simulations recapitulate previous findings that selection on the RHD deletion is frequency dependent, and weak or absent near 0.5. Therefore, once such a frequency was achieved, it could have been maintained by a relatively small amount of genetic drift. We unexpectedly observed evidence for positive selection on the C allele of RHCE in non-African populations (on chromosomes with intact copies of the RHD gene) in the form of an unusually high FST value and the high frequency of a single haplotype carrying the C allele. RhCE function is not well understood, but the C/c antigenic variant is clinically relevant and can result in hemolytic disease of the newborn, albeit much less commonly and severely than that related to the D-negative blood type. Therefore, the potential fitness benefits of the RHCE C allele are currently unknown but merit further exploration.
doi:10.1007/s00439-012-1147-5
PMCID: PMC3378649  PMID: 22367406
Blood group polymorphism; copy number variation; human evolution; balancing selection
17.  Acute hemolytic transfusion reactions due to multiple alloantibodies including anti-E, anti-c and anti-Jkb. 
Journal of Korean Medical Science  2003;18(6):894-896.
We report a case of two consecutive episodes of acute hemolytic transfusion reactions (HTRs) due to multiple alloantibodies in a 34-yr-old man who suffered from avascular necrosis of left femoral head. He received five units of packed red blood cells (RBCs) during surgery. Then the transfusion of packed RBCs was required nine days after the surgery because of the unexplained drop in hemoglobin level. The transfusion of the first two units resulted in fever and brown-colored urine, but he received the transfusion of another packed RBCs the next day. He experienced even more severe symptoms during the transfusion of the first unit. We performed antibody screening test, and it showed positive results. Multiple alloantibodies including anti-E, anti-c and anti-Jkb were detected by antibody identification study. Acute HTRs due to multiple alloantibodies were diagnosed, and the supportive cares were done for 6 days. We suggest the antibody screening test should be included in the panel of pretransfusion tests for safer transfusion, and it is particularly mandatory for the patients with multiple transfusions, pregnant women, and preoperative patients.
PMCID: PMC3055152  PMID: 14676451
18.  Severe intracranial haemorrhage in neonatal alloimmune thrombocytopenia 
BMJ Case Reports  2011;2011:bcr0720114563.
Neonatal alloimmune thrombocytopenia is a rare (1/1000–5000 births) life-threatening disorder, caused by fetomaternal incompatibility for a fetal human platelet alloantigen inherited from the father, with production of maternal alloantibodies against fetal platelets, leading to severe thrombocytopenia and potential bleeding. Intracranial haemorrhage is the most feared complication. This report presents the case of a term newborn infant, born from caesarean section after a normal pregnancy, presenting signs of skin bleeding with different ages. Obstetric history included a previous spontaneous abortion after amniocentesis. Severe thrombocytopenia (4×109/l platelets) was found and brain ultrasound showed multiple intracranial haemorrhages. Human platelet antigen (HPA) phenotyping showed maternal negative HPA-1a and paternal positive HPA-1a platelets. Strongly positive anti-HPA-1a and weakly positive anti-human leukocyte antigen class I alloantibodies were found in the mother. Multiple platelet transfusions, intravenous immunoglobulin and corticosteroid were given but favourable response was accomplished only after a compatible platelet transfusion. Brain MRI showed multiple subacute and chronic haemorrhages.
doi:10.1136/bcr.07.2011.4563
PMCID: PMC3176384  PMID: 22679192
19.  Donor Funding for Newborn Survival: An Analysis of Donor-Reported Data, 2002–2010 
PLoS Medicine  2012;9(10):e1001332.
With recent increases in development assistance money for maternal and child health, Catherine Pitt and colleagues examine whether foreign aid specifically for newborns has changed, whether it's on par with the burden of newborn deaths worldwide, and how such funding can be tracked.
Background
Neonatal mortality accounts for 43% of global under-five deaths and is decreasing more slowly than maternal or child mortality. Donor funding has increased for maternal, newborn, and child health (MNCH), but no analysis to date has disaggregated aid for newborns. We evaluated if and how aid flows for newborn care can be tracked, examined changes in the last decade, and considered methodological implications for tracking funding for specific population groups or diseases.
Methods and Findings
We critically reviewed and categorised previous analyses of aid to specific populations, diseases, or types of activities. We then developed and refined key terms related to newborn survival in seven languages and searched titles and descriptions of donor disbursement records in the Organisation for Economic Co-operation and Development's Creditor Reporting System database, 2002–2010. We compared results with the Countdown to 2015 database of aid for MNCH (2003–2008) and the search strategy used by the Institute for Health Metrics and Evaluation. Prior to 2005, key terms related to newborns were rare in disbursement records but their frequency increased markedly thereafter. Only two mentions were found of “stillbirth” and only nine references were found to “fetus” in any spelling variant or language. The total value of non-research disbursements mentioning any newborn search terms rose from US$38.4 million in 2002 to US$717.1 million in 2010 (constant 2010 US$). The value of non-research projects exclusively benefitting newborns fluctuated somewhat but remained low, at US$5.7 million in 2010. The United States and the United Nations Children's Fund (UNICEF) provided the largest value of non-research funding mentioning and exclusively benefitting newborns, respectively.
Conclusions
Donor attention to newborn survival has increased since 2002, but it appears unlikely that donor aid is commensurate with the 3.0 million newborn deaths and 2.7 million stillbirths each year. We recommend that those tracking funding for other specific population groups, diseases, or activities consider a key term search approach in the Creditor Reporting System along with a detailed review of their data, but that they develop their search terms and interpretations carefully, taking into account the limitations described.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 1990, 12 million children—most of them living in developing countries—died before they reached their fifth birthday. Faced with this largely avoidable loss of young lives, in 2000, world leaders set a target of reducing under-five mortality (deaths) to one-third of its 1990 level by 2015 as Millennium Development Goal 4 (MDG4); this goal, together with seven others, aims to eradicate extreme poverty globally. In recent years, progress towards reducing child mortality has accelerated but remains insufficient to achieve MDG4, in part, because progress towards reducing neonatal mortality—deaths during the first 28 days of life—has been particularly slow. Neonatal deaths now account for a greater proportion of global child deaths than in 1990—43% of the 7 million children who died before their fifth birthday in 2011 died during the neonatal period. The major causes of neonatal deaths are complications of preterm and term delivery and infections. Simple interventions such as improved hygiene at birth and advice on breastfeeding can substantially reduce neonatal deaths.
Why Was This Study Done?
To achieve MDG4, more must be done to prevent deaths among newborn babies. One reason that progress in reducing neonatal mortality is slow could be insufficient donor funding (aid) for newborn health. Previous analyses by, for example, Countdown to 2015 (which tracks coverage levels for health interventions that reduce maternal, newborn, and child mortality) indicate that donor funding has increased for maternal, newborn, and child health over the past decade, but how much of this aid directly benefits newborns is unknown. Here, the researchers develop a method for tracking aid flows for newborns and examine changes in this flow over the past decade by applying their new strategy to the Organisation for Economic Co-operation and Development (OECD) Creditor Reporting System (CRS) Aid Activity database. This database collects information about official development assistance for health given (disbursed) to developing countries by member countries of the OECD Development Assistance Committee, international organizations, and some private donors.
What Did the Researchers Do and Find?
The researchers developed a comprehensive set of search terms related to newborn survival by piloting it on the Countdown to 2015 official development assistance database, which covers the years 2003–2008. They then used their list of 24 key terms to search the CRS database from 2002 (the first year for which relatively complete disbursement data are available) to 2010 (the most recent year for which data are available) and classified each retrieved project according to whether its funding activities aimed to benefit newborns exclusively or to improve the health of other population groups as well. The researchers found that key terms related to newborns were rare in disbursement records before 2005 but that their frequency increased markedly thereafter. The total value of non-research disbursements (aid provided for programmatic or advocacy activities) that mentioned any newborn search terms increased from US$38.4 million in 2002 to US$717.1 million in 2010. The value of non-research projects that exclusively benefitted newborns fluctuated; in 2010, it was $US5.7 million. Finally, the US and United Nations Children's Fund (UNICEF) provided the largest value of non-research funding mentioning newborns and exclusively benefitting newborns, respectively.
What Do These Findings Mean?
These findings indicate that the value of aid disbursements mentioning newborns or an activity likely to benefit newborns increased 20-fold between 2002 and 2010 and constituted an increasing proportion of aid for maternal, newborn, and child health. Although this increase may partly reflect increased detail in aid disbursement reporting, it is also likely to reflect an increase in donor attention to newborn survival. The accuracy of these findings is likely to be affected by limitations in the search strategy and in the CRS database, which does not capture aid flows from emerging donors such as China or from many private foundations. Moreover, because these findings take no account of domestic expenditure, they do not provide a comprehensive estimate of the value of resources available in developing countries for newborn health. Nevertheless, investment in newborn survival is unlikely to be commensurate with global newborn mortality. Thus, an expansion of programmatic funding from donors as well as increased governmental support for newborn health in developing countries is urgently needed to catalyze the scale-up of cost-effective interventions to save newborn lives and to meet MDG4.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001332.
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health, including the 2012 report of UN Inter-agency Group of Child Mortality Estimation; its Committing to Child Survival: a Promise Renewed webpage includes links to its 2012 progress report, to a video about progress made in reducing child deaths worldwide, and to stories about child survival in the field
The World Health Organization has information about Millennium Development Goal 4 and about maternal, newborn, child, and adolescent health (some information in several languages)
Countdown to 2015 provides additional information on maternal, newborn, and child survival, including its 2012 report Building a Future for Women and Children
The Healthy Newborn Network (HNN) is a community of more than 70 partner organizations addressing critical knowledge gaps for newborn health providing recent data on newborn survival and analyses of country programs
Information on and access to the Organisation for Economic Co-operation Development Creditor Reporting System Aid Activities database is available
Further information about the Millennium Development Goals is available
doi:10.1371/journal.pmed.1001332
PMCID: PMC3484125  PMID: 23118619
20.  Detection of fetal RhD gene from maternal blood 
Objective
Hemolytic disease of the newborn (HDN) is a clinic phenomenon which occurs during pregnancy due to the Rhesus (Rh) D alloimmunization between a Rh (−) pregnant woman, who has become sensitive to RhD antigens, and her Rh (+) fetus. As a result of the attack of maternal RhD antibodies on fetal RhD antigens, fetal anemia, HDN and fetal death may occur. % 40 of Rh (−) pregnant women carry Rh (−) fetus. However, all Rh (−) pregnant women are offered anti-D Immunoglobulin (Anti-D Ig) at 28 weeks’ gestation in case of fetomaternal haemorrhage, so the pregnant women carrying Rh (−) fetus are exposed to blood products unnecessarily. Although the RhD of fetus can be detected, methods used for prenatal diagnosis recently are invasive tests and they can result in abortion in a certain percentage. The discovery of circulating cell-free fetal nucleic acids in maternal plasma has opened up new possibilities for non invasive prenatal diagnosis. The aim of this study was to detect prenatal RhD by analysing the presence of the RhD gene of fetal DNA in maternal blood.
Material and Methods
Total free DNA was isolated from the blood of 19 Rh (−) pregnant women, who had RhD alloimmunization with their husbands, in the 11–14 th week of their pregnancy. The existence of a gene in isolated DNA was investigated with TaqMan prob and “Real-time PCR” method by using primers belonging to exon 7 of RhD gene.
Results
Using a quantitative real-time PCR assay, the presence of RhD gene sequences was evaluated in the serum of patients at the onset of pregnancy. We have analyzed 19 Rh (−) pregnant women. Twelve of them were Rh (−) and the rest of them were 7 Rh (+). After birth the baby’s blood groups were concordant with our results.
Conclusion
The results obtained by RhD primer were analysed. The possibility of detection of fetal RhD gene in maternal blood contributed to noninvasive prenatal diagnosis.
doi:10.5152/jtgga.2010.04
PMCID: PMC3939095  PMID: 24591904
Fetal DNA; RhD gene; real-time PCR
21.  Can Prenatal Malaria Exposure Produce an Immune Tolerant Phenotype?: A Prospective Birth Cohort Study in Kenya 
PLoS Medicine  2009;6(7):e1000116.
In a prospective cohort study of newborns residing in a malaria holoendemic area of Kenya, Christopher King and colleagues find a subset of children born to malaria-infected women who acquire a tolerant phenotype, which persists into childhood and is associated with increased susceptibility to malarial infection and anemia.
Background
Malaria in pregnancy can expose the fetus to malaria-infected erythrocytes or their soluble products, thereby stimulating T and B cell immune responses to malaria blood stage antigens. We hypothesized that fetal immune priming, or malaria exposure in the absence of priming (putative tolerance), affects the child's susceptibility to subsequent malaria infections.
Methods and Findings
We conducted a prospective birth cohort study of 586 newborns residing in a malaria-holoendemic area of Kenya who were examined biannually to age 3 years for malaria infection, and whose malaria-specific cellular and humoral immune responses were assessed. Newborns were classified as (i) sensitized (and thus exposed), as demonstrated by IFNγ, IL-2, IL-13, and/or IL-5 production by cord blood mononuclear cells (CBMCs) to malaria blood stage antigens, indicative of in utero priming (n = 246), (ii) exposed not sensitized (mother Plasmodium falciparum [Pf]+ and no CBMC production of IFNγ, IL-2, IL-13, and/or IL-5, n = 120), or (iii) not exposed (mother Pf−, no CBMC reactivity, n = 220). Exposed not sensitized children had evidence for prenatal immune experience demonstrated by increased IL-10 production and partial reversal of malaria antigen-specific hyporesponsiveness with IL-2+IL-15, indicative of immune tolerance. Relative risk data showed that the putatively tolerant children had a 1.61 (95% confidence interval [CI] 1.10–2.43; p = 0.024) and 1.34 (95% CI 0.95–1.87; p = 0.097) greater risk for malaria infection based on light microscopy (LM) or PCR diagnosis, respectively, compared to the not-exposed group, and a 1.41 (95%CI 0.97–2.07, p = 0.074) and 1.39 (95%CI 0.99–2.07, p = 0.053) greater risk of infection based on LM or PCR diagnosis, respectively, compared to the sensitized group. Putatively tolerant children had an average of 0.5 g/dl lower hemoglobin levels (p = 0.01) compared to the other two groups. Exposed not sensitized children also had 2- to 3-fold lower frequency of malaria antigen-driven IFNγ and/or IL-2 production (p<0.001) and higher IL-10 release (p<0.001) at 6-month follow-ups, when compared to sensitized and not-exposed children. Malaria blood stage–specific IgG antibody levels were similar among the three groups.
Conclusions
These results show that a subset of children exposed to malaria in utero acquire a tolerant phenotype to blood-stage antigens that persists into childhood and is associated with an increased susceptibility to malaria infection and anemia. This finding could have important implications for malaria vaccination of children residing in endemic areas.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Each year, Plasmodium falciparum, a mosquito-borne parasite, causes about 500 million cases of malaria and about one million people die as a result. Most of these deaths occur in young children in sub-Saharan Africa. Indeed, malaria accounts for a fifth of all childhood deaths in Africa, which makes it one of the most important childhood infectious diseases in this region. Very young children—those up to 6 months old—are relatively resistant to high-density parasitaemia and to clinical malaria, but children between 6 and 36 months old have an increased susceptibility to parasitaemia and to clinical malaria. Parasitaemia is the presence of P. falciparum parasites in the blood; a high density of blood-stage parasites causes the symptoms of clinical malaria (including high fever) and life-threatening organ damage and anemia (a lack of red blood cells).
Why Was This Study Done?
The age-dependent pattern of susceptibility to malaria suggests that young babies are protected by antibodies provided by their mothers, but that by 6 months old, when these antibodies have largely disappeared, babies have not yet fully developed their own anti-malaria immunity. However, little is known about the acquisition of anti-malaria immunity in infants, a process that needs to be understood in order to design effective vaccines for this age group. In particular, it is unclear how maternal malaria infection affects the acquisition of anti-malaria immunity. Malaria in pregnancy may expose the unborn child to malaria-infected red blood cells and to soluble malaria antigens (molecules that the immune system recognizes as foreign). This exposure could increase or decrease the child's immune responses to blood-stage malaria antigens and thus affect his/her ability to fight off malaria. In this study, the researchers investigated how prenatal malaria exposure affects anti-malaria immunity in young children and their susceptibility to subsequent malaria infections.
What Did the Researchers Do and Find?
The researchers determined which of 586 newborn babies enrolled into their study in an area of Kenya where malaria is very common had been exposed to P. falciparum before birth by looking for parasites in their mother's blood at delivery. They looked for malaria-specific immune responses in T cells (a type of immune system cell) in the newborn babies' cord blood by measuring the production of cytokines (molecules that either activate or inhibit the immune system) by these cells after exposure to malaria antigens. Finally, they examined the infants twice yearly for 3 years for malaria infection, malaria-specific immune responses, and anemia. The researchers classified the babies into three groups; cord blood cells of “sensitized” babies made activating cytokines in response to malaria antigens; cord blood cells of “exposed, not-sensitized” babies did not make activating cytokines but made an inhibitory cytokine (IL-10); and “not-exposed” babies were born to mothers with no P. falciparum infection at delivery. In their first 3 years of life, the exposed, not-sensitized group had a 60% greater risk of malaria infection (measured by counting parasites in their blood) than the unexposed group and a slightly higher risk of malaria infection than the sensitized group. They also had lower hemoglobulin levels (a sign of anemia) than the other babies. At age 6 months, the T cells of exposed, not-sensitized children were less likely to make activating cytokines in response to malaria antigens but made more IL-10 than the T cells of the other children; malaria-specific antibody levels were similar in the three groups.
What Do These Findings Mean?
These findings suggest that some children who are exposed to malaria before birth become “tolerant” to blood-stage malaria antigens. Exposure to malaria antigens before birth “tricks” their T cells into recognizing these antigens as self antigens. This immune tolerance, which persists into childhood, reduces the ability of the immune system to attack and destroy parasites and increases the susceptibility of these tolerant children to malaria infection. Why some children who are exposed to malaria before birth become tolerant while exposure to malaria antigens “primes” the immune system of other children to respond efficiently to these antigens is not clear. However, these findings could have important implications for the design of malaria vaccines for use in areas where children are often exposed to malaria before birth and for the design of strategies for the prevention of malaria during pregnancy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000116.
This study is further discussed in a PLoS Medicine Perspective by Lars Hviid
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy and on children and malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000116
PMCID: PMC2707618  PMID: 19636353
22.  Efficacy of Short-Course AZT Plus 3TC to Reduce Nevirapine Resistance in the Prevention of Mother-to-Child HIV Transmission: A Randomized Clinical Trial 
PLoS Medicine  2009;6(10):e1000172.
Neil Martinson and colleagues report a randomized trial of adding short-course zidovudine+lamivudine to reduce drug resistance from single-dose nevirapine used to prevent mother-to-child transmission of HIV.
Background
Single-dose nevirapine (sdNVP)—which prevents mother-to-child transmission of HIV—selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care.
Methods and Findings
sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1∶1∶1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit.
Conclusions
A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms.
Trial registration
www.ClinicalTrials.gov NCT 00144183
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 33 million people are infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV can be treated with combination antiretroviral therapy (ART), commonly three individual antiretroviral drugs that together efficiently suppress the replication of the virus. HIV infection of a child by an HIV-positive mother during pregnancy, labor, delivery, or breastfeeding is called mother-to-child transmission (MTCT). In 2007, an estimated 420,000 children were newly infected with HIV, the majority through MTCT. Most of these mothers and children live in sub-Saharan Africa where child and maternal mortality rates are high and mortality in HIV-infected children is extremely high. MTCT is preventable and there is a global commitment, agreed at the UN General Assembly Session on HIV/AIDS in 2001, to reduce the proportion of infants infected with HIV by 50% by 2010.
Why Was This Study Done?
In many resource-limited settings, MTCT is prevented by giving a single dose of nevirapine (an antiretroviral drug which has a long duration in the body and protects the fetus during labor and delivery only) to HIV-infected women in labor and also to a baby within 72 hours of birth. However, nevirapine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), which suppresses the replication of the virus, is associated with increased resistance of HIV, in mother and child, to NNRTI. This resistance reduces the effectiveness of future treatments of both mother and child with combination ART that includes an NNRTI; such regimens are the mainstay for long-term treatment of HIV in developing countries. The researchers investigated whether giving other antiretroviral drugs with nevirapine, during labor and delivery, to both mother and her newborn reduced the chances of them developing resistance to NNRTIs.
What Did the Researchers Do and Find?
The researchers selected 406 HIV-positive pregnant women for study across five sites in South Africa between February 2003 and May 2007. The women and their newborn babies were randomly assigned to receive, either (i) a single dose of nevirapine, (ii) a single dose of nevirapine plus combivir (zidovudine combined with lamivudine) for four days, or (iii) a single dose of nevirapine plus combivir for seven days. At two days, two weeks, and six weeks after delivery blood was collected from mothers and babies. HIV virus from blood samples was analyzed for resistance mutations, and mothers and children with resistance mutations were monitored for a further 96 weeks until no resistance was detected or combination ART (also called “HAART”) was started. Enrollment into the single-dose nevirapine arm was stopped early because a very high rate of NNRTI resistance mutations was found and other investigators reported long-term bad consequences of NNRTI-resistance on subsequent ART. The two nevirapine plus combivir arms were continued. The researchers found that selection of resistance mutations by single-dose nevirapine was reduced in mother and child by the addition of zidovudine and lamivudine for a short period; resistance mutations were found in 59.2% of women who got nevirapine only but only 11.7%, and 7.3% of women treated nevirapine plus four days combivir, and nevirapine plus seven days combivir respectively. A reduction was also seen in new NNRTI resistant mutations in the HIV-infected infants that received combivir. The study did not have enough women to show that there was a real difference between the resistance in the four-day and seven-day combivir regimens.
What Do These Findings Mean?
These findings show that a short-course treatment of zidovudine and lamivudine in addition to a single dose of nevirapine during labor and birth reduces the selection of NNRTI resistance mutations in both mother and child. The drug regimens appeared safe, and easy to provide and adhere to. Preliminary results from this study contributed to a change in clinical practice for the care of pregnant women with HIV; in 2004 the World Health Organisation guidelines introduced a short course of combivir with nevirapine for the management of pregnant HIV-infected women. However, the study had some limitations. It used HIV-positive women who were mainly infected with a subtype of HIV called HIV-1 clade C and who had a lot of virus in their blood. NNRTI resistance after treatment with nevirapine is more common in clade C than in others and this study does not address the effect of these combinations for preventing NNRTI resistance in other HIV subtypes. Also, World Health Organization, national, and international guidelines recommend combination ART during pregnancy, as it decreases HIV transmission from mother to child in the uterus to <2% in resource-limited settings. Although long-term combination treatment may not be available in all locations, this study does not tell us how the short-term combinations during and after delivery tested would compare to longer-term combinations given to pregnant women in reducing both HIV transmission and HIV drug resistance.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000172.
This study is further discussed in a PLoS Medicine Perspective by Lehman et al.
The US Centers for Disease Control and Prevention provide information for HIV treatment and prevention
MedlinePlus provides extensive information on symptoms and treatment for HIV/AIDS as well as access to related clinical trials and medical literature
aidsmap, a nonprofit, nongovernmental organization provides information on HIV and supporting those living with HIV
The World Health Organization gives information on the prevention of mother-to-child transmission of HIV
doi:10.1371/journal.pmed.1000172
PMCID: PMC2760761  PMID: 19859531
23.  Severe hydrops in the infant of a Rhesus D-positive mother due to anti-c antibodies diagnosed antenatally: a case report 
Introduction
Rhesus haemolytic disease of the newborn is a prototype of maternal isoimmunisation and fetal haemolytic disease. There are other rare blood group antigens capable of causing alloimmunisation and haemolytic disease such as c, C, E, Kell and Duffy. In India, after the confirmation of a newborn's blood group, antibodies are screened only if the mother is Rehsus D-negative negative and the father is Rhesus D-positive. Hydrops in Rhesus positive women are investigated along the lines of non-immune hydrops.
Case presentation
We report the case of a patient from India where irregular antibodies were requested for an O-positive 26-year-old mother in order to investigate fetal hydrops. Anti-c antibody was revealed and the fetus was treated successfully with compatible O negative and c negative intrauterine blood transfusions. The baby was treated postnatally with double volume exchange transfusion with the same compatible blood, and was discharged 30 days after birth.
Conclusion
We highlight the importance of conducting irregular antibody screening for women with significant obstetric history and fetal hydrops. This could assist in diagnosing and successfully treating the fetus with appropriate antigen negative cross-matched compatible blood. We note, however, that anti-c immunoglobulin is not yet readily available.
doi:10.1186/1752-1947-4-57
PMCID: PMC2830983  PMID: 20167104
24.  A Case of Neonatal Alloimmune Neutropenia Associated with Anti-Human Neutrophil Antigen-1a (HNA-1a) Antibody 
Journal of Korean Medical Science  2006;21(2):351-354.
Neonatal alloimmune neutropenia (NAN) is an uncommon disease of the newborn provoked by the maternal production of neutrophil-specific alloantibodies, whereby neutrophil IgG antibodies cross the placenta and induce the destruction of fetal neutrophils. Affected newborns are usually identified by the occurrence of bacterial infections. The most frequent antigens involved in NAN are the human neutrophil antigen-1a (HNA-1a), HNA-1b, and HNA-2a. We report a neonate who was delivered at 36 weeks and had a severe neutropenia but who responded well to recombinant human granulocyte colony-stimulating factor (rhG-CSF). Anti-HNA-1a antibody was identified by mixed passive hemagglutination assay in both the sera of the baby and the mother. The baby had HNA-1a and HNA-1b but the mother had only HNA-1b on granulocytes. This is the first Korean report of NAN in which the specificity of the causative antibody was identified.
doi:10.3346/jkms.2006.21.2.351
PMCID: PMC2734018  PMID: 16614528
Infant, Newborn; Neutropenia; neutrophil-specific antigen NA1, human; Antibodies
25.  Two Years' Experience with Rh Hemolytic Disease Reporting 
California Medicine  1973;118(5):28-32.
California law, since January 1 1970, has required that all pregnant women, regardless of outcome of delivery, be tested for Rho(D) type, that the mother and physician be notified of the result and that hospitals providing service to newborns report all cases of Rho(D) Hemolytic Disease to the State Department of Public Health. Although there has been only a gradual decrease in the number of deaths due to Rho(D) Hemolytic Disease of the Newborn since 1950, there has been a precipitous fall in the past two years. Since the commencement of reporting of the disease to the State Health Department the number of cases has also dropped dramatically. It is felt that because of our conscientiously administered reporting law the morbidity and mortality figures from HDN in California are accurate, in contrast to results obtained in most other states.
It is believed that this report reflects the first really accurate look at a large population for the incidence and mortality from Rho(D) HDN since the advent of widespread use of anti-Rho(D) gamma globulin. Review of the recent literature failed to reveal definitive data on recent incidence and mortality trends for Rho(D) HDN. A survey of state health departments also failed to produce data comparable with California's.
A number of factors have played a part in reducing the incidence and mortality from Rho(D) HDN in California—namely, required testing of pregnant women combined with the almost routine use of of anti-Rho(D) immune globulin in eligible women, early recognition and treatment of Rho(D) HDN, and the reduction in family size with an increasing percentage of primiparous mothers.
PMCID: PMC1455062  PMID: 4633598

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