condition diagnosed prenatally, but that concept is so wide and would include so many existing different procedures as to be unhelpful. For example, prophylactic measures (like anti-D globulin for Rhesus disease or corticosteroids for fetal lung maturation), actions during labour in cases of suspected fetal hypoxia (Caesarean section, amnio-infusion, tocolysis) and medical and surgical treatments on the mother (treatment of perinatal infections, nutrient supplementation) could all be included.
The application of evidence-based medicine to fetal therapy is limited at present. The rarity of many of the conditions in which fetal therapy is used often makes randomised studies impractical, and so meta-analysis or systematic reviews are not possible. Observational studies have demonstrated significant improvements in the outcomes in some clinical situations after prenatal diagnosis and therapy. Fetal therapy is currently entering a new era of larger and more wide-spread implementation and evidence-based evaluation. This chapter concentrates on those conditions and interventions that seem to have clear clinical benefit and brief mention of the others.
TRANSFUSION THERAPY IN HAEMATOLOGICAL CONDITIONS
FETAL ANAEMIAIntra-uterine intraperitoneal transfusion, was originally described by Liley,1
mainly in fetuses with hydrops and low gestational age, and was associated
29
José L. BarthaMD, Consultant Senior Lecturer, Fetal Medicine Research Unit, University of Bristol,
Department of Obstetrics and Gynaecology, St Michael’s Hospital, Southwell Street, Bristol BS2 8SR, UK
Peter W. SoothillPhD, Professor of Maternal and Fetal Medicine, University of Bristol, Department
of Clinical Medicine, St Michael’s Hospital, Southwell Street, Bristol BS2 8EG, UK (for correspondence)
José L. Bartha Peter W. Soothill
3
Clinical applications of
with a poor survival rate. To improve the outcomes, Rodeck et al.2designed a
new procedure based on intravascular transfusion under the direct vision of fetoscopy. However, this procedure also had a high risk for fetal loss. In the early 1980s, Bang et al.3described a new method of umbilical cord needling
under ultrasound guidance. The procedure was widely developed during the 1980s and is currently the first choice for intravascular access.
Fetal transfusion is undertaken by puncturing the umbilical vein, usually at placental cord insertion, with a 20–22-gauge needle after local anaesthesia in the maternal abdominal wall. Some centres use paralyzing agents such as vecuronium to stop fetal movements when sampling intrafetal vessels but, in our experience, this is rarely needed. A sample of fetal blood is obtained to determine the pretransfusion haemoglobin concentration. Adult blood, irradiated (to prevent graft versushost rejection) and packed to a hematocrit of 75–85% (to reduce volume), is used. Some authors have used maternal blood as the source of red cells in order to obtain theoretical benefits in terms of decreasing the risk for sensitization to new red-cell antigens,4but this has not
been demonstrated to be beneficial. The amount of blood to be transfused to restore the haemoglobin concentration back to normal can be calculated by applying established mathematical formulae, often using computer programmes. During transfusion, the visualization of the turbulence caused by the injected blood entering the umbilical vein confirms that the blood is being infused correctly. The volume needed is given as fast as possible without causing a bradycardia since the placenta seems to help the fetus to manage this blood volume expansion.
Transfusions are repeated depending on the rate of hematocrit drop. The use of non-invasive techniques, such as middle cerebral artery Doppler,4to
predict fetal haemoglobin concentrations facilitates the timing of the next transfusion. Using intra-uterine intravascular transfusions, the overall survival rate is about 84%,6reaching near 100% in cases of non-hydropic fetuses. Before
the era of intra-uterine transfusion, an immunized woman had a 50% chance of losing her baby, the effect of the clinical application of fetal therapy in this field is clear.7
Parvo-virus B19 infection can also cause a severe fetal anaemia leading, in the most severe cases, to fetal hydrops and death. The virus causes arrest of maturation of red blood cell precursors at the late normoblast stage and also a decrease in the number of platelets. In addition, myocarditis leading to heart failure may contribute to the development of fetal hydrops. Reported data suggest a benefit of transfusion therapy over conservative management in infected fetuses especially in severe cases.8
FETAL THOMBOCYTOPENIA
In allo-immune thrombocytopenia, fetal platelets are destroyed by maternal antibodies directed against platelet antigens, mainly HPA-1a or HPA-5a. In the affected neonates, 10–20% develop intracranial haemorrhage, with 25–50% of these occurring prenatally.9 Investigation is often by fetal blood sampling at
18–22 weeks which may be repeated at 28–32 weeks if the fetus is not seriously affected earlier. Therapeutic options include maternal administration of intravascular immunoglobulin, corticosteroid therapy and fetal platelet
Recent Advances in Obstetrics and Gynaecology 22
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Clinical applications of fetal therapy
transfusion. The latter may also be used prophylactically at each fetal blood sampling to avoid bleeding during the procedure. However, the transfused platelet life-span is only about 4–5 days and weekly transfusions may be needed to control the disease. Cumulative risk for fetal loss of serial weekly transfusions is approximately 6% per pregnancy, which indicates the need for development of less invasive approaches.10
The relative risk reduction in mortality with antenatal therapy is 57% (95% CI, 0.19–0.77).11 Treatment of pregnancies with intravenous immunoglobulin
increased the likelihood of a neurologically normal outcome, with a relative risk of 1.68 (95% CI, 1.3–2.2), and treatment of pregnancies with only antenatal platelet transfusions increased the likelihood of a neurologically normal outcome with a relative risk of 1.63 (95% CI, 1.1–2.1). Further studies are needed to determine the relative roles of fetal platelet transfusions and maternal administration of immunoglobulin in the perinatal outcomes. Because fetal blood sampling is difficult before 20 weeks, in cases at risk of very early fetal intracranial haemorrhage (i.e. where a sibling has suffered an intracranial haemorrhage prior to 20 weeks), treatment of the mother with intravenous immunoglobulin (1 g/kg/week or more) seems justifiable from around 16 weeks’ gestation.12