Antenatal prophylaxis of Rh isoimmunization: 28-weeks'-gestation service program

Two (0.18%) of 1086 Rh-negative primigravidas or multigravidas treated similarly in all previous pregnancies, who were given a single injection of Rh immune globulin (300 μg) at 28 weeks'' gestation and subsequently were delivered of Rh-positive babies, had demonstrable Rh isoimmunization at the time of that injection and must be considered “logistic” failures of antenatal prophylaxis. The remaining 1084 (who were treated again after delivery) had no evidence of Rh isoimmunization at delivery and none of the 512 screened at 6 months after delivery appeared to be immunized. If the 28th-week injection had not been protective, one would have expected 14 of the 1084 to have been demonstrably Rh isoimmunized and evidence of Rh isoimmunization to have persisted in 6 of the 512 observed 6 months after delivery.Six of 719 Rh-negative multigravidas who had not received Rh immune globulin after previous pregnancies or had been treated only after delivery showed evidence of Rh isoimmunization despite a single injection of Rh immune globulin at 28 weeks in a subsequent pregnancy. In three of the six the cause was most likely “sensibilization” due to previous exposure to Rh-positive blood or an untreated Rh-positive pregnancy. in 3 of the remaining 716 (0.42%) there may have been true failure of antenatal Rh prophylaxis administered at the 28th week. One would have expected this figure to be 12 of 716 if antenatal Rh prophylaxis at 28 weeks'' gestation were totally unsuccessful.It is concluded that a single intramuscular injection of Rh immune globulin, 300 μg, is 88% effective in preventing Rh isoimmunization during pregnancy in Rh-negative primigravidas and in multigravidas treated antenatally in all previous pregnancies, and is 75% effective in preventing Rh isoimmunization in Rh-negative multigravidas untreated during previous pregnancies. The majority of failures are due to Rh isoimmunization during pregnancy prior to antenatal prophylaxis at 28 weeks.     

Incidence of rhesus immunisation after genetic amniocentesis.

Of 655 Rh negative women without anti-D antibody in their serum at genetic amniocentesis, 361 delivered a Rh positive infant. Prophylactic treatment with anti-D immunoglobulin was not given at amniocentesis. The women were followed prospectively, being given a screening test for antibody after amniocentesis, at delivery, and six months later. Five of these 361 women yielded a positive test result due to anti-D antibody. The immunisation rate after genetic amniocentesis was no higher than the spontaneous immunisation rate during pregnancy. Four women who had two amniocenteses in the same pregnancy and 34 women who had amniocentesis in two consecutive pregnancies with Rh positive fetuses were not immunised. Among six women with anti-D antibody in their serum before amniocentesis the titre of antibody increased in three. Amniocentesis may have worsened the outcome of these pregnancies. These results suggest that the risk of immunisation in Rh negative women is small.     

Rh immunization in Manitoba: progress in prevention and management.

For two decades the perinatal mortality caused by erythroblastosis has been decreasing in Manitoba. The improved management of Rh-immunized pregnancies has lowered the death rate among affected infants from 10.8% to 3.4%, while the prevention of Rh immunization has reduced its incidence from 9.1 to 2.2 per 1000 total births. In its first 6 years and 8 months Manitoba''s antenatal prophylaxis program, in which immunoglobulin is administered to Rh-negative women at 28 weeks'' gestation, reduced the incidence of Rh immunization during pregnancy by 93%. In combination with post-abortion and postpartum prophylaxis the antenatal treatment has provided a protection rate of 98.6% among primigravidas at risk. Further improvements are expected.     

Prevention of Rh haemolytic disease.

Between 1970 and 1976 in the Yorkshire region the incidence of Rh antibodies in Rh-negative pregnant women fell by 70%. This decrease occurred in both old (long-standing) and new (first-affected) cases, which emphasised that the reduction in numbers was as much due to fewer pregnancies among Rh-negative mothers as to administration of anti-D immunoglobulin. Nevertheless, the incidence has begun to level out. The continued incidence of first-affected cases is caused by three main factors: failure of administration of anti-D immunoglobulin after normal deliveries and abortions; a steady incidence of antibodies in primigravidae; and cases in which administration of anti-D immunoglobulin had failed to protect. Administering anti-D antenatally might reduce the incidence of new cases among primigravidae who are sensitised before anti-D is normally given. Even without routine antenatal administration of anti-D, the incidence of severely affected Rh babies in the Yorkshire region could be reduced to one or two isolated cases a year in a population of three to four million by administering anti-D after all Rh-negative deliveries and after every abortion.     

Rh isoimmunization during pregnancy: antenatal prophylaxis.

Of 3533 Rh-negative women who began a pregnancy without detectable Rh antibodies, 62 (1.8%) demonstrated evidence of Rh isoimmunization during pregnancy or within 3 days after delivery. All denied transfusions as well as abortions or previous pregnancies not followed by the administration of Rh immune globulin. Rh isoimmunization during pregnancy or within 3 days after delivery, which will not be prevented by the administration of Rh immune globulin after delivery, is the most important cause of residual Rh isoimmunization. A clinical trial of antenatal administration of Rh immune globulin, initially at 34 weeks''s and subsequently at 28 and 34 weeks'' gestation, in 1357 Rh-negative pregnant women who were delivered of Rh-positive babies, was effective in preventing the development of Rh isoimmunization during pregnancy or within 3 days after delivery. Antenatal prophylaxis with Rh immune globulin will be necessary if the incidence of Rh isoimmunization is to be reduced to its lowest possible level. Antenatal prophylaxis at 28 weeks'' gestation is now an insured service in Manitoba.     

Reduced severity of Rh-haemolytic disease after anti-D immunoglobulin.

A total of 2459 Rh-negative women who received anti-D immunoglobulin after a Rh-positive pregnancy were followed up in at least one subsequent pregnancy. There was a failure of protection rate of 1-6%. Follow-up of 53 subsequent infants of mother in whom protection had failed showed that the infants were less severely affected than would have been expected. This was confirmed by a comparative statistical analysis of the present series and a series of first affected cases before anti-D immunoglobulin was available, using the antibody titre during pregnancy and the haemoglobin levels at delivery.     

Association between Foeto-maternal Bleeding and Hypertension in Pregnancy

A blind prospective survey of foeto-maternal bleeding in 200 primiparous pregnancies was carried out in an investigation of a possible association between foeto-maternal bleeding and hypertension in pregnancy. Evidence of foeto-maternal bleeding was found in 61% of 36 hypertensive pregnancies, and in 51% of 160 normotensive pregnancies, a difference which is not statistically significant.Significant differences between the hypertensive and the normotensive groups were found when foeto-maternal bleeding was related to gestation. In pregnancies that became hypertensive more foetal cells were found in the maternal circulation before week 36 than in normotensive pregnancies. In patients with oedema of the abdominal wall during pregnancy the incidence of foeto-maternal bleeding was significantly increased.These findings seem to explain why pre-eclamptic toxaemia is a significant predisposing factor in women who later develop Rh antibodies. It is recommended that anti-D gammaglobulin should be offered to all Rh-negative women with Rh-positive infants following a hypertensive pregnancy. Consideration should also be given to the question of administering anti-D gammaglobulin during Rh-negative hypertensive pregnancies if this procedure is proved to be both safe to mother and foetus and effective.The results provide contributory evidence that the placental vascular changes in toxaemic pregnancies precede the clinical signs and are not the result of hypertension.     

Prevention of Rh-haemolytic Disease: Final Results of the “High-risk” Clinical Trial: A COMBINED STUDY FROM CENTRES IN ENGLAND AND BALTIMORE

The final results are reported of a trial of about 1,000 μg of anti-D gammaglobulin given intramuscularly to a selected high-risk group of Rh-negative primiparae just delivered of an ABO-compatible Rh-positive baby, the aim being to prevent them becoming immunized to Rh. Six months after delivery only 1 out of 173 treated mothers had been immunized as against 38 out of 176 controls. The crucial test of the prophylactic therapy depends on the presence or otherwise of anti-D at the end of a second Rh-positive pregnancy. Of 86 treated mothers two had antibodies at this time compared with 20 out of 65 controls.The results show a high degree of protection in this group of mothers.     

Prevention of Rh Hemolytic Disease of the Newborn

Rh_o(D)-Immune Globulin was given to 322 Rh-negative women delivered of ABO-compatible, Rh-positive infants with no apparent failures to suppress Rh sensitization. In contrast, 32 of 305 mothers of a control group made Rh antibody during the six months following delivery. In subsequent pregnancies, 69 women administered RhoGAM had no evidence of isoimmunization after delivery while six of forty mothers of the control study produced anti-Rh. RhoGAM, given within 72 hours of delivery in the amounts employed, was effective for suppression of Rh immunization.     

Prevention of Rh-haemolytic Disease: Results of the Liverpool “Low-risk” Clinical Trial

A clinical trial is reported in which Rh-negative primiparae, just delivered of an Rh-positive ABO-compatible infant and in whom fetal cell counts after delivery suggested less than 0·2 ml of circulating fetal blood, were treated with about 200 μg of anti-D gammaglobulin. Three (0·36%) out of 844 women thus treated developed anti-D in the subsequent six months; this is 10% of the incidence in untreated controls. Three (1·8%) out of 171 treated mothers had anti-D at the end of the second Rh-positive pregnancy, and this is 18% of the incidence in controls.Possible reasons for the occasional failure of the treatment are discussed and the results of this trial are compared with those of a previous trial in which 1,000 μg or more of anti-D was given to a different group of mothers. The combined results of the two trials lead to the conclusion that the passive administration of anti-D gammaglobulin after delivery affords in this population of Rh-negative women a 95% protection rate in the postdelivery period and an 89% protection rate by the end of the subsequent pregnancy.     

Anti-erythrocyte immunization in the pregnant woman. Apropos of the analysis of 761 cases of alloimmunized women delivered in the Paris area in 1978 and 1979

Through analysis of 760 cases of allo-immunized women delivered in the Paris area during 1978 and 1979, anti-erythrocyte immunization (ABO excluded) still appears to be a consequent perinatal risk, for the mother as for her fetus. During the considered period, general incidence in the parisian population has been of 3,78 for 1 000 livebirths, one out of four cases being a "non Rh D"immunization. Obviously, anti-D immunoglobulin prophylaxis has not proved to be as efficient as it promised to be, after more than ten years of application. Taking into account cases affecting "non ordinary" residents in the observed area, incidence of anti-D immunizations was of two out of a thousand. Anti-D immunoglobulin actual efficiency cannot be incriminated, for when correctly applied Rhesus immunization prophylaxis has demonstrated its ability to induce a twenty-fold reduction of immunization risk due to pregnancy. It must be pointed out, unfortunately, that most cases of undue immunizations are related to prophylatic omissions after delivery, miscarriage, abortion or fortuitous hetero-Rhesus blood transfusion. On another hand an important increase of "non Rh D" immunizations, which incidence, if one images that unknown cases are as frequent as known cases, could be two out of a thousand deliveries, is perhaps able to neutralize partially the decrease of Rh D immunizations. Though is underlined the absolute necessity to extend systematically anti-erythrocyte antibody screenings to all pregnant women, whatever the blood group is. A great variety of antibodies specificities can be found among "on Rh D" immunizations but anti-Kell and anti-c are by far the most frequently met. In most cases theses immunizations could easily be avoided, assessing that all female subjects aged less than 50 years are only given Kell negative and, if lacking c antigen, CC phenotyped blood.     

High-risk pregnancy in rhesus monkeys (Macaca mulatta): a case of ectopic, abdominal pregnancy with birth of a live, term infant, and a case of gestational diabetes complicated by pre-eclampsia

Background  Cases of abdominal pregnancy, in the form of intra-abdominal mummified fetuses, have been described in nonhuman primates. Gestational diabetes and pre-eclampsia are common pregnancy complications in women.
Methods  Two timed-bred rhesus monkeys had high-risk pregnancies, an abdominal pregnancy with delivery of a live term infant, and a case of gestational diabetes that later developed pre-eclampsia.
Results  The monkey that had abdominal pregnancy later died from septic peritonitis. The monkey had a colonic adenocarcinoma that may have allowed leakage of intestinal contents into the abdomen. Her infant was fostered to another female and survived. The monkey with gestational diabetes and pre-eclampsia was treated with a regimen similar to that used in women, and a live infant was delivered at day 157 of gestation by Caesarian section.
Conclusion  These cases underscore the value of timed-breeding and the similarities between pregnancy complications in women and in nonhuman primates.     

Factors associated with the intellectual ability of children born to women with high risk pregnancies.

The intellectual abilities of 242 children born to women who had been hypertensive during pregnancy were assessed at the age of 7 1/2 years. Associations between 15 maternal, fetal, perinatal, postnatal and environmental factors, and test scores were investigated. After adjustment for confounding variables children in the upper social classes, born to non-smokers, who were first born, breast fed, and with birth weights above the 10th centile had significantly higher scores in some aspects of ability than the rest. Children whose mothers had developed superimposed pre-eclampsia had higher scores than those whose mothers had not suffered preeclampsia; and children delivered by elective caesarean section had lower scores than those delivered spontaneously. In a small subgroup of women with particularly high risk pregnancies perinatal mortality had been 10 times greater than in the rest of the sample. At 7 1/2 years the intellectual ability of the survivors in this subgroup did not differ from that of the rest. These findings do not support the notion that there is a quantitative continuum of "reproductive casualty" from mortality to morbidity.     

Relationships of risk factors for pre-eclampsia with patterns of occurrence of isolated gestational proteinuria during normal term pregnancy

Background

Isolated gestational proteinuria may be part of the pre-eclampsia disease spectrum. Confirmation of its association with established pre-eclampsia risk factors and higher blood pressure in uncomplicated pregnancies would support this concept.

Methods

Data from 11,651 women from the Avon Longitudinal Study of Parents and Children who had a term live birth but did not have pre-existing hypertension or diabetes or develop gestational diabetes or preeclampsia were used. Proteinuria was assessed repeatedly (median 12 measurements per woman) by dipstick and latent class analysis was used to identify subgroups of the population with different patterns of proteinuria in pregnancy.

Results

Higher maternal pre-pregnancy body mass index (BMI), younger age, nulliparity and twin pregnancy were independently associated with increased odds of any proteinuria in pregnancy. Women who experienced proteinuria showed five patterns: proteinuria in early pregnancy only (≤20 weeks gestation), and onset at 21–28 weeks, 29–32 weeks, 33–36 weeks and ≥37 weeks gestation. There were higher odds of proteinuria onset after 33 weeks in obese women and after 37 weeks in nulliparous women compared with normal weight and multiparous women respectively. Smoking in pregnancy was weakly negatively associated with odds of proteinuria onset after 37 weeks. Twin pregnancies had higher odds of proteinuria onset from 29 weeks. In women with proteinuria onset after 33 weeks blood pressure was higher in early pregnancy and at the end of pregnancy.

Conclusions

Established pre-eclampsia risk factors were related to proteinuria occurrence in late gestation in healthy term pregnancies, supporting the hypothesis that isolated gestational proteinuria may represent an early manifestation of pre-eclampsia.     

Maternal and feto-placental prostanoid responses to a single course of antenatal betamethasone

We tested the hypothesis that antenatal betamethasone alters prostanoid levels in the maternal and feto-placental compartments. Forty-three singleton pregnancies were studied. Group I were women treated with a single course of antenatal betamethasone and who delivered <37 weeks gestation; Group II were untreated women who delivered <37 weeks; and Group III were untreated women who delivered >38 weeks. Maternal and mixed cord blood; and placental samples were collected at delivery and analyzed for PGE2, PGF(2alpha), 6-ketoPGF(1alpha), and TxB2 levels. Antenatal betamethasone decreased maternal PGE2 levels with concomitant increases in the feto-placental compartment. Umbilical cord TxB2 levels in the treated group were significantly lower than the non-treated pre-term and term groups resulting in a higher 6-ketoPGF(1alpha):TxB2 ratio. Considering the regulatory role of PGE2 and PGI2 in fetal lung development and neonatal transition homeostasis, these results suggest a mechanism, at least in part, for the beneficial effects of antenatal steroids on fetal lung maturation and neonatal cardio-pulmonary homeostasis at birth.     

WinRho: Rh immune globulin prepared by ion exchange for intravenous use.

An Rh immune globulin [Rh IgG] for intravenous use, WinRho, has been prepared by the Winnipeg Rh Institute by a modification of the ion-exchange column method of Hoppe and colleagues. When administered to Rh-negative male and nonpregnant female volunteers WinRho was found to be nonpyrogenic, nontoxic, safe and protective against Rh alloimmunization. In a clinical trial with 240 microgram given at about 28 weeks'' gestation and 120 microgram given after delivery to Rh-negative women at risk of Rh immunization WinRho was effective in preventing Rh immunization. Of the 870 women carrying Rh-positive fetuses who were treated with WinRho during pregnancy and were not tested several months after delivery 14 would have shown evidence of Rh immunization by the time of delivery if WinRho had been ineffective; none showed such evidence. Of the 1122 women carrying Rh-positive fetuses who were retested 4 to 6 months after delivery 83 would have shown evidence of Rh immunization at that time if WinRho had been ineffective; only 1 showed such evidence. The efficiency of yield of anti-D with the modified method of production, the fct that it can be given intravenously (a route that causes the patient less discomfort and immediately results in high anti-D levels) and the lower levels of contaminating IgA and IgM make WinRho the preparation of choice for preventing Rh immunization.     

Prospective study of human parvovirus (B19) infection in pregnancy. Public Health Laboratory Service Working Party on Fifth Disease.

OBJECTIVE--To determine the fetal infection rate and outcome of pregnancy among women who acquire infection with human parvovirus (B19) in the antenatal period. DESIGN--Prospective study of infected pregnancies till time of delivery or abortion with virological investigation of fetuses, neonates, and 1 year old infants. SETTING--England and Wales during 1985-8. PATIENTS--190 Pregnant women with serologically confirmed B19 infection in pregnancy, their fetuses, neonates, and 1 year old infants. RESULTS--Of 186 mothers who elected to go to term, 156 (84%) delivered a normal baby. Follow up of 114 of these infants to the age of 1 year disclosed no appreciable abnormalities, although 27 had serological evidence of intrauterine infection. The overall fetal loss rate (30 cases; 16%) was similar to that in an uninfected antenatal sample (unmatched), but there was a pronounced excess of fetal loss in the second trimester in the B19 infected mothers (11.8%; 95% confidence interval 6.8% to 17.8%). Based on virological findings in the aborted fetuses the risk of fetal death due to B19 in an infected pregnancy was estimated to be 9%. The transplacental transmission rate was estimated to be 33%. CONCLUSIONS--Most women with B19 infection in pregnancy had a satisfactory outcome, but there was nevertheless a substantial risk of fetal loss in the second trimester. In view of the absence to date of any evidence of damage to babies who survive maternal infection therapeutic termination of pregnancy is not indicated.     

Deaths from rhesus haemolytic disease in England and Wales in 1982 and 1983.

Examination of death certificates and the clinical notes of the patients concerned showed that the number of deaths from rhesus (D) haemolytic disease in England and Wales was 44 and 34 during 1982 and 1983, respectively, a substantial decrease from the figure of 106 for 1977. Of the 78 women whose infants died in 1982 and 1983, 49 had not received anti-Rh immunoglobulin after previous pregnancies with Rh positive infants; most of these deaths would presumably have been prevented had postnatal anti-Rh immunoglobulin been given. In 13 women anti-D was detected during, or immediately after, a first pregnancy, and in 15 women rhesus immunisation developed despite administration of anti-Rh immunoglobulin postnatally. One or two apparent failures of treatment may have been due to underdosage, but it must be concluded that about one third of the deaths in 1982 and 1983 could have been prevented only by giving anti-Rh immunoglobulin antenatally as well as postnatally.     

Targeted Routine Antenatal Anti-D Prophylaxis in the Prevention of RhD Immunisation - Outcome of a New Antenatal Screening and Prevention Program

Objective

To estimate the incidence of RhD immunisation after implementation of first trimester non-invasive fetal RHD screening to select only RhD negative women carrying RHD positive fetuses for routine antenatal anti-D prophylaxis (RAADP).

Materials and Methods

We present a population-based prospective observational cohort study with historic controls including all maternity care centres and delivery hospitals in the Stockholm region, Sweden. All RhD negative pregnant women were screened for fetal RHD genotype in the first trimester of pregnancy. Anti-D immunoglobulin (250–300 µg) was administered intramuscularly in gestational week 28–30 to participants with RHD positive fetuses. Main outcome measure was the incidence of RhD immunisation developing during or after pregnancy.

Results

During the study period 9380 RhD negative women gave birth in Stockholm. Non-invasive fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed in 8374 pregnancies of which 5104 (61%) were RHD positive and 3270 (39%) RHD negative. In 4590 pregnancies with an RHD positive test the women received antenatal anti-D prophylaxis. The incidence of RhD immunisation in the study cohort was 0.26 percent (24/9380) (95% CI 0.15–0.36%) compared to 0.46 percent (86/18546) (95% CI 0.37 to 0.56%) in the reference cohort. The risk ratio (RR) for sensitisation was 0.55 (95% CI 0.35 to 0.87) and the risk reduction was statistically significant (p = 0.009). The absolute risk difference was 0.20 percent, corresponding to a number needed to treat (NNT) of 500.

Conclusions

Using first trimester non-invasive antenatal screening for fetal RHD to target routine antenatal anti-D prophylaxis selectively to RhD negative women with RHD positive fetuses significantly reduces the incidence of new RhD immunisation. The risk reduction is comparable to that reported in studies evaluating the outcome of non selective RAADP to all RhD negative women. The cost-effectiveness of this targeted approach remains to be studied.     

Plasmodial pigmentation of placenta and outcome of pregnancy in West African mothers.

In a region where falciparum malaria is endemic and where pregnant women traditionally receive only curative treatment for parasitaemias and no chemoprophylaxis 65 placental biopsy specimens were examined histologically for malaria pigment. Twenty seven placentas had pigment, but parasitaemias had been diagnosed antenatally in only 12 of these women despite their frequent attendance at antenatal and other clinics. The incidence of parasitaemia in pregnant primigravidas was 17.7%, seven times greater than that in lactating primiparous mothers; pregnant primigravidas also had the highest incidence (67%) of pigmented placentas. First born babies with pigmented placentas had a mean (SD) birth weight of 2580 (260) g, significantly less than the 3150 (400) g of unaffected first babies. All babies weighing less than 2500 g at birth had pigmented placentas. Pigmentation was associated with parasitaemias in the second half of pregnancy, and, although some recovery from early parasitaemias may occur, the fetoplacental unit is inadequately protected by curative treatment alone. Chemoprophylaxis currently remains the procedure of choice.