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-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.     

An error in Rh testing in pregnancy.

Anti-D (anti-Rho) in the blood of two Rh-negative pregnant women was believed to be due to active immunization. In the first case, however, antibodies were no longer detectable 2 weeks later. In the second case they disappeared by the end of 31 weeks. It was discovered that both women had been given immune globulin (human) because of exposure to rubella. The globulin given to the first woman probably contained about 0.1 mug of anti-D per ml; that given to the second probably contained about 0.6 mug of anti-D per ml. Both babies were O Rh-positive. Both women were given Rh immune globulin after delivery. Both have completed a further pregnancy and no anti-D has been found on many tests. In tests carried out in 1971 all samples of immune globulin (human) examined contained anti-D, but usually in inconsequential trace amounts.     

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.     

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.     

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.     

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.     

Incidence of Maternal Rh Immunization by ABO Compatible and Incompatible Pregnancies

The incidence of maternal Rh immunization in Rh-negative women following a single ABO compatible Rh-positive pregnancy is about 17%. This incidence was determined by following Rh-negative women through two Rh-incompatible pregnancies and analysing their sera for anti-Rh at the time of delivery of their second observed pregnancy. Maternal Rh immunization occurs almost exclusively after delivery; however, antibodies may not be detectable in the absence of further antigenic stimulation.The incidence of maternal Rh immunization when maternal-foetal ABO incompatibility is also present is 9–13% and 17% for group O and non-group O women respectively. This study emphasizes the need to offer Rh-immune prophylaxis to Rh-negative women having Rh-positive infants whether or not ABO incompatibility exists between the mother and infant.     

Efficacy and long term effects of antenatal prophylaxis with anti-D immunoglobulin.

OBJECTIVE--To measure the safety and efficacy of antenatal treatment with anti-D immunoglobulin. DESIGN--Open study with historical controls. SETTING--Multicentre study in 17 hospitals in West Yorkshire. PATIENTS--1238 Rh negative women who delivered Rh positive infants after 34 weeks in their first pregnancy in 1980-1 (group 1) and 2000 similar primigravidas from 1978-9 (group 2). Obstetric data were collected for 616 women in group 1 who had a subsequent pregnancy, 536 similar women in group 2, and 410 Rh positive but otherwise similar primigravidas who delivered in the same hospitals in 1978-81 (group C). INTERVENTIONS--Anti-D immunoglobulin 100 micrograms intramuscularly was given at 28 and 34 weeks to the mothers in their first pregnancy who delivered in 1980-1. END POINTS--Detection of anti-D antibody in the first or any subsequent pregnancy in groups 1 and 2. For all three groups having subsequent pregnancies gestation at delivery, birth weight, fetal survival at one month, pre-eclampsia defined as blood pressure greater than 140/90 on two occasions more than 12 hours apart, and proteinuria greater than 0.25 milligram. MEASUREMENTS AND MAIN RESULTS--Antenatal immunisation to Rh(D) occurred in six mothers in group 1 and 32 group 2. Most immunisations occurred in the first or second pregnancy. The rates of abortion, gestation at delivery, birth weight, and fetal survival were not significantly different among the three groups. The incidence of pre-eclampsia was lower in mothers given antenatal anti-D immunoglobulin, but the difference was not significant. CONCLUSIONS--Antenatal prophylaxis with anti-D immunoglobulin is effective, and the effect of giving it in the first pregnancy persists into at least the second pregnancy. It seems to be safe for the fetus in the index and subsequent pregnancies.     

Clinical Evaluation of Rh0(D) Immune Globulin (Human) in Canada

—During 1966, clinical trials were conducted in three Canadian centres to determine the safety and efficacy of Rh₀(D) immune globulin (human) in preventing isoimmunization by the Rh₀(D) antigen in Rh-negative women delivering ABO-compatible Rh-positive infants.The candidates were randomly divided into control and treated groups; the treated mothers received an intramuscular injection of 300 μg. of anti-Rh₀(D) within 72 hours of delivery. Follow-up antibody screening tests were conducted on the sera of all patients six to nine months post partum.Of the 175 control patients, 11 or 6.2% became actively immunized to the Rh antigen, whereas complete protection against maternal Rh immunization was observed in the 191 treated patients.     

Glycosylated haemoglobin concentrations in mothers of large babies.

Mothers who have big babies may have had abnormal glucose tolerance during pregnancy. Glycosylated haemoglobin (HbA1) concentrations were measured on the first or second day after delivery in 50 women who had had babies weighing over the 95th centile for gestational age and in 50 women who had had normal-sized babies (controls). Nine of the mothers of big babies but only one of the controls had an HbA1 concentration above the normal range. All the women had normal glucose tolerance and HbA1 concentrations six weeks after delivery. Measuring HbA1 concentration in the first two days after delivery in mothers of large babies may identify gestational diabetics.     

Uptake,Outcomes, and Costs of Antenatal,Well-Baby,and Prevention of Mother-to-Child Transmission of HIV Services under Routine Care Conditions in Zambia

Background

Zambia adopted Option A for prevention of mother-to-child transmission of HIV (PMTCT) in 2010 and announced a move to Option B+ in 2013. We evaluated the uptake, outcomes, and costs of antenatal, well-baby, and PMTCT services under routine care conditions in Zambia after the adoption of Option A.

Methods

We enrolled 99 HIV-infected/HIV-exposed (index) mother/baby pairs with a first antenatal visit in April-September 2011 at four study sites and 99 HIV-uninfected/HIV-unexposed (comparison) mother/baby pairs matched on site, gestational age, and calendar month at first visit. Data on patient outcomes and resources utilized from the first antenatal visit through six months postpartum were extracted from site registers. Costs in 2011 USD were estimated from the provider’s perspective.

Results

Index mothers presented for antenatal care at a mean 23.6 weeks gestation; 55% were considered to have initiated triple-drug antiretroviral therapy (ART) based on information recorded in site registers. Six months postpartum, 62% of index and 30% of comparison mother/baby pairs were retained in care; 67% of index babies retained had an unknown HIV status. Comparison and index mother/baby pairs utilized fewer resources than under fully guideline-concordant care; index babies utilized more well-baby resources than comparison babies. The average cost per comparison pair retained in care six months postpartum was $52 for antenatal and well-baby services. The average cost per index pair retained was $88 for antenatal, well-baby, and PMTCT services and increased to $185 when costs of triple-drug ART services were included.

Conclusions

HIV-infected mothers present to care late in pregnancy and many are lost to follow up by six months postpartum. HIV-exposed babies are more likely to remain in care and receive non-HIV, well-baby care than HIV-unexposed babies. Improving retention in care, guideline concordance, and moving to Option B+ will result in increased service delivery costs in the short term.     

Weight growth in infants born to mothers who smoked during pregnancy.

OBJECTIVE--To determine whether maternal smoking during pregnancy causes impairment in growth after birth. DESIGN--Longitudinal study. SETTING--Six medical university centres of six towns of north, central, and south Italy. SUBJECTS--12,987 babies (10,238 born from non-smoking mothers, 2276 from mothers smoking one to nine cigarettes a day, and 473 from mothers smoking > or = 10 cigarettes a day) entered the study. MAIN OUTCOME MEASURES--Difference in weight gain between children born to smoking mothers and those born to non-smoking mothers. Weight was measured at birth and at 3 and 6 months of age. Maternal smoking habit was derived from interview on third or fourth day after delivery. RESULTS--Compared with children born to mothers who did not smoke during pregnancy, the birth weights of children born to mothers who smoked up to nine cigarettes a day were 88 g (girls) and 107 g (boys) lower; in children born to mothers who smoked > or = 10 cigarettes a day weights were 168 g and 247 g lower. At six months of age for the first group the mean weight for girls was 9 g (95% confidence interval -47 g to 65 g) higher and for boys 64 g (-118 g to -10 g) lower than that of children born to mothers who did not smoke. The corresponding figures for the second group were 28 g (-141 g to 85 g) lower for girls and 24 g (-136 g to 88 g) lower for boys. CONCLUSIONS--The deficits of weight at birth in children born to mothers who smoked during pregnancy are overcome by 6 months of age. These deficits are probably not permanent when smoking habit during pregnancy is not associated with other unfavourable variables (such as lower socioeconomic class).     

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.     

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.     

Lymphocyte function in patients with anti-D(Rh0) antibodies

The behaviour of humoral and cellular immunity as well as that of cells bearing Fc receptors was investigated in persons with anti-D antibodies. Peripheral lymphocytes could be identified in 6 of 26 examined test persons particularly sensitized against the stroma of Rh-positive erythrocytes. There was no relation to the anti-D titre. The parameters of humoral immunity showed no correlation to the anti-D titre. In 37 per cent of the persons with anti-D antibodies, which were produced "naturally" or artificially, an increased content of IgE could be proved in the serum. In each case, anti-D formation apparently leads to an increase of cells bearing Fc receptors, which can be recognized by the increased number of EA rosettes. A relation to the anti-D titre did not exist. None of the immunological test methods used is suitable for predicting the success of an artificial immunization for the purpose of gaining high titre anti-D antibodies.     

Mercury accumulation in placenta and foetal membranes. A study of dental workers and their babies.

To investigate the hazards of exposure to levels of elemental mercury lower than the present TLV value (0.05 mg/m3) a group of dental workers and a nonexposed group were studied. The amount of mercury in blood from mothers and babies at the time of delivery was similar. The exposed group had increased mercury content in placenta and foetal membranes. Mercury accumulation in these organs might serve as a protection for the foetus against mercury exposure. Since exposure to sub-TLV concentrations of elemental mercury during pregnancy will not be reflected in blood mercury content at the time of delivery, the amount of mercury in placenta and foetal membranes might serve as a biological indicator of such exposure.     

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.