Neonatal and Obstetrical Outcomes of Pregnancies Complicated by Alloimmunization.

BACKGROUND AND OBJECTIVES: Despite advances in the prevention of rhesus (Rh)(D) alloimmunization, alloantibodies to Rh(D) and non-Rh(D) red blood cell antigens continue to be detected in ∼4% of US pregnancies and can result in hemolytic disease of the fetus and newborn (HDFN). Recent reports on HDFN lack granularity and are unable to provide antibody-specific outcomes. The objective of this study was to calculate the frequency of alloimmunization in our large hospital system and summarize the outcomes based on antibody specificity, titer, and other clinical factors. METHODS: We identified all births in a 6-year period after a positive red blood cell antibody screen result during pregnancy and summarized their characteristics and outcomes. RESULTS: A total of 707 neonates were born after a positive maternal antibody screen result (3.0/1000 live births). In 31 (4%), the positive screen result was due to rhesus immune globulin alone. Of the 676 neonates exposed to alloantibodies, the direct antibody test (DAT) result was positive, showing antigen-positivity and evidence of HDFN in 37% of those tested. Neonatal disease was most severe with DAT-positive anti-Rh antibodies (c, C, D, e, E). All neonatal red blood cell transfusions (15) and exchange transfusions (6) were due to anti-Rh alloimmunization. No neonates born to mothers with anti-M, anti-S, anti-Duffy, anti-Kidd A, or anti-Lewis required NICU admission for hyperbilirubinemia or transfusion. CONCLUSIONS: Alloimmunization to Rh-group antibodies continues to cause a majority of the severe HDFN cases in our hospital system. In neonates born to alloimmunized mothers, a positive DAT result revealing antigen-positivity is the best predictor of anemia and hyperbilirubinemia.

Alloimmune hemolytic disease of the fetus and newborn: genetics, structure, and function of the commonly involved erythrocyte antigens.

Hemolytic disease of the fetus and newborn (HDFN) can occur when a pregnant woman has antibody directed against an erythrocyte surface antigen expressed by her fetus. This alloimmune disorder is restricted to situations where transplacental transfer of maternal antibody to the fetus occurs, and binds to fetal erythrocytes, and significantly shortens the red cell lifespan. The pathogenesis of HDFN involves maternal sensitization to erythrocyte "non-self" antigens (those she does not express). Exposure of a woman to a non-self-erythrocyte antigen principally occurs through either a blood transfusion or a pregnancy where paternally derived erythrocyte antigens, expressed by her fetus, enter her circulation, and are immunologically recognized as foreign. This review focuses on the genetics, structure, and function of the erythrocyte antigens that are most frequently involved in the pathogenesis of alloimmune HDFN. By providing this information we aim to convey useful insights to clinicians caring for patients with this condition.

Impact of smoking during pregnancy on functional coagulation testing.

Compounds that are systemically absorbed during the course of cigarette smoking, and their metabolites, affect the coagulation system and cause endothelial dysfunction, dyslipidemia, and platelet activation leading to a prothrombotic state. In addition, smoking increases the activity of fibrinogen, homocysteine, and C-reactive protein. We hypothesize that smoking may affect functional coagulation testing during pregnancy. A secondary analysis of 371 women pregnant with a singleton pregnancy and enrolled in a multicenter, prospective observational study of complications of factor V Leiden mutation subsequently underwent functional coagulation testing for antithrombin III, protein C antigen and activity, and protein S antigen and activity. Smoking was assessed by self-report at time of enrollment (<14 weeks). None of the functional coagulation testing results was altered by maternal smoking during pregnancy. Smoking does not affect the aforementioned functional coagulation testing results during pregnancy.

The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications. METHODS AND FINDINGS: A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06-2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89-1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80-1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79-1.99) or SGA (OR 1.25, 95% CI 0.92-1.70). CONCLUSIONS: Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants. Please see later in the article for the Editors' Summary.

Avascular villi, increased syncytial knots, and hypervascular villi are associated with pregnancies complicated by factor V Leiden mutation.

There is controversy about whether pathologic abnormalities are associated with pregnancies complicated by factor V Leiden (FVL) mutation. The purpose of this study was to evaluate 105 placentas delivered to mothers heterozygous for FVL mutation to determine if there are pathologic changes suggestive of hypoxia or thrombosis, which correlate with mutation status. We examined placentas obtained as part of a prospective study of 5188 pregnancies analyzed for the presence of FVL mutation in either the mother or the infant. One hundred five placentas from mothers heterozygous for the mutation were compared with 225 controls matched for maternal age, race, and geographic site. Of the 330 pregnancies, 50 infants were FVL mutation heterozygotes. Maternal FVL heterozygote status was associated with more frequent increased numbers of syncytial knots (13% vs 4%); the difference remained significant after controlling for hypertension, preeclampsia, small-for-gestational-age infants, and delivery prior to 35 weeks of gestation (odds ratio 3.6, 95% confidence interval 1.5-8.7, P  =  0.004). Maternal FVL heterozygotes had more hypervascular villi (10% vs 3%), with significance retained controlling for delivery route (odds ratio 3.4, 95% confidence ratio 1.2-9.4, P  =  0.018). Placentas from infants heterozygous for FVL mutation had more avascular villi than controls (odds ratio 2.9, 95% confidence interval 1.5-5.6, P  =  0.001). Fetal or maternal FVL heterozygosity was not associated with infarcts, small-for-gestational-age placentas, or fetal thrombotic vasculopathy. This analysis demonstrates that pathologic findings associated with placental hypoxia, specifically focal avascular villi, increased numbers of syncytial knots, and hypervascular villi, also correlate with FVL heterozygosity in infants or mothers.

Family history of venous thromboembolism and identifying factor V Leiden carriers during pregnancy.

OBJECTIVE: To estimate whether there is a correlation between family history of venous thromboembolism and factor V Leiden mutation carriage in gravid women without a personal history of venous thromboembolism. METHODS: This is a secondary analysis of a prospective observational study of the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden mutation. Family history of venous thromboembolism in either first- or second-degree relatives was self-reported. Sensitivity, specificity, and positive and negative predictive values of family history to predict factor V Leiden mutation carrier status were calculated. RESULTS: Women without a personal venous thromboembolism history and with available DNA were included (n=5,168). One hundred forty women (2.7% [95% confidence interval (CI) 2.3-3.2%]) were factor V Leiden mutation-positive. Four hundred twelve women (8.0% [95% CI 7.3-8.7%]) reported a family history of venous thromboembolism. Women with a positive family history were twofold more likely to be factor V Leiden mutation carriers than those with a negative family history (23 of 412 [5.6%] compared with 117 of 4,756 [2.5%], P<.001). The sensitivity, specificity, and positive predictive value of a family history of a first- or second-degree relative for identifying factor V Leiden carriers were 16.4% (95% CI 10.7-23.6%), 92.3% (95% CI 91.5-93.0%), and 5.6% (95% CI 3.6-8.3%), respectively. CONCLUSION: Although a family history of venous thromboembolism is associated with factor V Leiden mutation in thrombosis-free gravid women, the sensitivity and positive predictive values are too low to recommend screening women for the factor V Leiden mutation based solely on a family history.

The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus.

OBJECTIVE: We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. METHODS: Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. RESULTS: One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0-2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02-0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were observed between FVL mutation carriers, carriers of other coagulation disorders, and controls. Maternal FVL mutation carriage was not associated with increased pregnancy loss, preeclampsia, placental abruption, or small for gestational age births. However, fetal FVL mutation carriage was associated with more frequent preeclampsia among African-American (15.0%) and Hispanic (12.5%) women than white women (2.6%, P = .04), adjusted odds ratio 2.4 (95% confidence interval 1.0-5.2, P = .05). CONCLUSION: Among women with no history of thromboembolism, maternal heterozygous carriage of the FVL mutation is associated with a low risk of venous thromboembolism in pregnancy. Neither universal screening for the FVL mutation, nor treatment of low-risk carriers during pregnancy is indicated. LEVEL OF EVIDENCE: II-2.

A molecular variant of angiotensinogen is associated with idiopathic intrauterine growth restriction.

OBJECTIVE: Intrauterine growth restriction has been associated with failed maternal physiologic changes such as abnormal spiral artery remodeling and reduced maternal blood volume. A polymorphism of angiotensinogen Thr235 has been considered a risk factor for preeclampsia. We genotyped maternal and fetal deoxyribonucleic acid (DNA) for angiotensinogen Thr235 to estimate whether the polymorphism is also a risk factor for intrauterine growth restriction. METHODS: We examined maternal blood DNA in 174 patients with intrauterine growth restriction and 60 patients with both preeclampsia and intrauterine growth restriction. The control group comprised 400 consecutive cases of women with term pregnancies and infants with birth weight between the fifth and 95th percentiles. We also examined 162 DNA samples from fetal blood with intrauterine growth restriction for the Thr235 polymorphism, and 240 normal fetuses were used as the control group. The angiotensinogen genotype was determined using mutagenically separated polymerase chain reaction. The products were size fractionated on an agarose gel. Angiotensinogen genotypes were divided into three groups: MM (homozygous for angiotensinogen Met235 allele), TT (homozygous for angiotensinogen Thr235 allele), and MT (heterozygous). RESULTS: Maternal genotyping revealed a significantly higher Thr235 allele frequency in intrauterine growth restriction (.60) and preeclampsia/intrauterine growth restriction (.63) than in the control group (.36) (P <.001). Fetal genotyping revealed a Thr235 allele frequency of.59 in intrauterine growth restriction fetuses, as compared with the control group (.38) (P <.001). CONCLUSION: Maternal and fetal angiotensinogen Thr235 genotypes are associated with an increased risk of intrauterine growth restriction in our study population. The angiotensinogen Thr235 allele may predispose women to deliver growth-restricted fetuses.

Cerebral perfusion pressure, and not cerebral blood flow, may be the critical determinant of intracranial injury in preeclampsia: a new hypothesis.

OBJECTIVE: The relationship between cerebral perfusion pressure (CPP) and cerebral blood flow is unclear in preeclampsia. Our objective was to clarify this issue by comparing normal pregnant women to those with mild and severe preeclampsia. STUDY DESIGN: Patients with mild (n = 72) and severe (n = 120) preeclampsia underwent transcranial Doppler (TCD) imaging of the maternal middle cerebral artery (MCA). At the same time, blood pressure was taken with a Dinamap monitor (Dinamap; Criticon Inc, Tampa, Fla). CPP, resistance area product (RAP), and the cerebral flow index (CFI) were calculated by standard formulas. Data were plotted on normative curves for pregnancy (5% and 95%) and compared by chi(2) and Mann-Whitney U tests. RESULTS: CFI is usually normal in both severe (75%) and mild (72%) cases. If CFI is abnormal in severe cases, it may be either increased (14%) or decreased (10%), although in mild cases almost all abnormal CFI (25%) is lower than normal. In those cases with low or normal CFI, severe cases are associated with a significantly higher CPP, RAP, and MAP than mild cases (P <.05), although the CFI is not significantly different. A significant proportion of severe cases have high CPP (52%), whereas in mild cases the CPP is almost always normal (87%). Overall, in severe cases the RAP is abnormally high, although it is within the normal range in mild cases. CONCLUSIONS: One of the fundamental differences between mild and severe cases relates to the degree of cerebral perfusion pressure that the MCAs are subjected to. Because most preeclamptic women, regardless of degree of severity, have a normal CFI, it appears that autoregulation is generally intact. Because women with severe cases are more prone to cerebral catastrophe than those with mild preeclampsia, uncontrolled CPP may cause barotrauma and vessel damage, leading to hypertensive encephalopathy and overperfusion injury. Therapeutic strategies that ensure reduction of the CPP with maintenance of the CFI seem most likely to prevent the cerebral injuries (overperfusion or underperfusion) that cause seizures or death in women with preeclampsia.

Labetalol decreases cerebral perfusion pressure without negatively affecting cerebral blood flow in hypertensive gravidas.

OBJECTIVE: To research the cerebral hemodynamic effects of labetalol in pregnant women with hypertension. DESIGN: Prospective observational study. SETTING: Tertiary Care Medical Center. POPULATION: Pregnant patients with hypertension. METHODS: Transcranial Doppler (TCD) ultrasound was used to measure the blood velocity in the middle cerebral arteries (MCA) of eight pregnant patients with hypertension, before and after the administration of a 200 mg oral dose of labetalol. Five patients had severe preeclampsia, and three had chronic hypertension with superimposed preeclampsia. MCA blood velocity and systemic blood pressure were measured simultaneously at the baseline, and at 60 and 180 min after labetalol. Selected cerebral hemodynamic parameters were compared with normative curves. Values outside of the 5th and 95th percentiles were regarded as abnormal. MAIN OUTCOME MEASURES: Cerebral perfusion pressure (CPP), resistance area product (RAP), and cerebral flow index (CFI). RESULTS: Patient age, gestational age, and parity were similar to those of the normal women from whom the normative data were obtained. Women with hypertension had higher baseline CPP, MAP, and RAP than normal pregnant women, but their CFI was within the normal range. Labetalol reduced the CPP, as well as the systolic, diastolic, and mean BP significantly at 60 and 180 min without significantly affecting the heart rate, MCA velocities, RAP, or CFI. CONCLUSIONS: Labetalol effectively reduces CPP, without affecting cerebral perfusion, primarily by a decrease in systemic blood pressure. This makes it an ideal agent for blood pressure control in severely hypertensive pregnant women.