Minimally-invasive fetal autopsy using magnetic resonance imaging and percutaneous organ biopsies: clinical value and comparison to conventional autopsy.

OBJECTIVES: Autopsy is an important investigation following fetal death or termination for fetal abnormality. Postmortem magnetic resonance imaging (MRI) can provide macroscopic information of comparable quality to that of conventional autopsy in the event of perinatal death. It does not provide tissue for histological examination, which may limit the quality of counseling for recurrence risks and elucidation of the cause of death. We sought to examine the comparability and clinical value of a combination of postmortem MRI and percutaneous fetal organ biopsies (minimally invasive autopsy (MIA)) with conventional fetal autopsy. METHODS: Forty-four fetuses underwent postmortem MRI and attempted percutaneous biopsy (using surface landmarks) of major fetal organs (liver, lung, heart, spleen, kidney, adrenal and thymus) following fetal death or termination for abnormality, prior to conventional autopsy, which was considered the 'gold standard'. We compared significant findings of the two examinations for both diagnostic information and clinical significance. Ancillary investigations (such as radiographs and placental histology) were regarded as common to the two forms of autopsy. RESULTS: In 21 cases conventional autopsy provided superior diagnostic information to that of MIA. In two cases the MIA provided superior diagnostic information to that of conventional autopsy, when autolysis prevented detailed examination of the fetal brain. In the remaining 21 cases, conventional autopsy and MIA provided equivalent diagnostic information. With regard to clinical significance, however, in 32 (72.7%) cases, the MIA provided information of at least equivalent clinical significance to that of conventional autopsy. In no case did the addition of percutaneous biopsies reveal information of additional clinical significance. CONCLUSIONS: Although in some cases MRI may provide additional information, conventional perinatal autopsy remains the gold standard for the investigation of fetal death. The utility of adding percutaneous organ biopsies, without imaging guidance, to an MRI-based fetal autopsy remains unproven. Postmortem MRI, combined with ancillary investigations such as placental histology, external examination by a pathologist, cytogenetics and plain radiography provided information of equivalent clinical significance in the majority of cases.

The relationship between first trimester fetal growth, pregnancy-associated plasma protein A levels and birthweight.

OBJECTIVE: We sought to define the relationship between first trimester fetal growth, pregnancy-associated plasma protein A (PAPP-A) levels and birthweight. METHODS: Two-hundred and one women with repeat first trimester crown-rump length (CRL) measurements were included. In 194, the first trimester PAPP-A value was known and in 169 there was complete data including birthweight. Fetal growth curves were derived using functional linear discriminant analysis (FLDA) and growth compared between those with < 10th percentile, 10th to 90th and > 90th percentile PAPP-A multiple of median (MoM) levels and birthweight percentiles. RESULTS: Median maternal age was 35 years, gestation at PAPP-A sampling and of first scan was 11 weeks. Median delivery gestation was 40 weeks and birthweight 3425 g. There was no association between first trimester fetal CRL growth and either PAPP-A MoM percentile or birthweight percentile. There was a significant positive correlation between PAPP-A MoM and birthweight percentile (p = 0.0004). CONCLUSIONS: First trimester fetal growth rate is not related to birthweight percentile or first trimester PAPP-A levels. Irrespective of gestation, a low PAPP-A is associated with delivery of a smaller baby, and a high PAPP-A with a larger baby.

Feasibility of percutaneous organ biopsy as part of a minimally invasive perinatal autopsy.

To determine the feasibility of percutaneous fetal organ biopsies in the context of a 'minimally invasive' perinatal autopsy after stillbirth and termination for abnormality is the aim of this study. We assessed successful biopsy rate and the proportion adequate for histological examination in 30 fetuses undergoing organ sampling before autopsy. The relationship between gestational age, body weight, death-biopsy interval, operator experience and successful biopsy rate was investigated. Significant findings from conventional block histology were compared with corresponding percutaneous biopsies. Of 210 organ biopsies attempted from seven target organs, 107 were obtained, of which 94 were adequate for pathological comment. The median delivery-autopsy interval was 4 (range 2-11) days. Adequate samples were obtained from the lung in 86% cases (95% CI 68, 96%), liver 76% (95% CI 56, 90%) and less frequently for the myocardium, kidney, adrenal, thymus and spleen. There was no relationship between biopsy success and time to biopsy, gestational age, body weight and user experience. No histological abnormalities found at autopsy were diagnosed from needle biopsies. Although targeted percutaneous biopsies appear feasible for some organs, fewer than 50% of all biopsies are adequate for histological examination. This technique cannot be considered to provide useful clinical information as part of a 'minimally invasive' perinatal autopsy.

The use of urinary albumin-creatinine ratios and calcium-creatinine ratios as screening tests for pregnancy-induced hypertension.

OBJECTIVE: To assess the potential of both urinary albumin creatinine ratios and urinary calcium-creatinine ratios as screening tests for pregnancy-induced hypertension. METHODS: A prospective, non-interventional study was performed in a teaching hospital antenatal clinic. Five hundred normotensive, nulliparous pregnant women provided a urine sample at 19 weeks' gestation. The main outcome measurements were the development of pregnancy-induced hypertension and preeclampsia. RESULTS: No significant differences in urinary albumin/creatinine and calcium/creatinine were demonstrated between patients who developed pregnancy-induced hypertension and those who remained normotensive. Urinary creatinine concentrations were significantly higher at 19 weeks' gestation in patients who subsequently developed pregnancy-induced hypertension. CONCLUSIONS: This study suggests that neither urinary ratio is a potential screening test for pregnancy-induced hypertension. The increased urinary creatinine concentration in patients who subsequently developed pregnancy-induced hypertension has not previously been reported and merits further investigation.

The effect of exercise on uteroplacental Doppler waveforms in normal and complicated pregnancies.

Animal studies have suggested a detrimental effect of exercise on uterine blood flow, but it is unclear whether the same responses occur in human pregnancy. Thirty-four women in the third trimester of singleton pregnancies underwent a bicycle exercise test during which a pulsed Doppler method was used to assess the response of the uteroplacental circulation. Twelve pregnancies were uncomplicated and the other 22 were complicated by hypertension, small for gestational age (SGA) fetus, or both. Exercise appeared to increase the pulsatility of the uteroplacental Doppler waveform in all cases. The changes in the waveforms were more exaggerated in the complicated pregnancies, particularly when the resting waveform had been abnormal. These changes indicate an increase in uteroplacental vascular resistance with exercise, suggesting a deleterious effect of physical exertion in the third trimester, particularly in the presence of hypertension or SGA fetus.

Tissue inhibitor of metalloproteinases: serum levels during pregnancy and labor, term and preterm.

OBJECTIVE: To determine the levels in serum of tissue inhibitor of metalloproteinases (TIMP) in pregnancy and to examine the possibility of a time course in relation to parturition, both term and preterm. METHODS: Serum tissue inhibitor of metalloproteinases was measured using an enzyme-linked immunosorbent assay. A cross-sectional study was conducted in 333 women during pregnancy, labor, and the postpartum period and in 27 nonpregnant volunteers. Longitudinal data were obtained from 22 women who provided a sample at term, during labor, and in the postpartum period. RESULTS: In uncomplicated pregnancies, serum TIMP levels were low from the onset of pregnancy until 37 weeks' gestation, in comparison to levels in nonpregnant women (P < .001). During the final weeks of pregnancy, levels rose and at 37-42 weeks were similar to nonpregnant levels. The levels did not change with the onset of labor. Serum concentrations of TIMP obtained during preterm labor were elevated compared to a control group of patients at a similar gestation who subsequently delivered at term (P < .01). Serum TIMP levels were significantly higher during the postpartum period than at all other times (P < .001). CONCLUSIONS: Changes in serum TIMP levels during and after pregnancy may parallel the remodeling of the extracellular matrix that takes place throughout this period. Further work is necessary to evaluate the prognostic value of TIMP for preterm labor.

Tissue collagenase: serum levels during pregnancy and parturition.

Serum levels of tissue collagenase, matrix metalloproteinase-1, were measured in both longitudinal and cross-sectional studies, in 332 pregnant women and 27 non-pregnant volunteers. The enzyme-linked immunosorbent assay (ELISA) used is the first described to measure collagenase in serum directly, is specific, and is rapid and reproducible. Levels were determined throughout pregnancy, during term and preterm labour, and in the post-partum period. Serum tissue collagenase levels were elevated in pregnancy (P < 0.001). There was no difference between levels of serum collagenase prior to labour at term and those observed during labour. Similarly, there was no significant difference in levels obtained during preterm labour and those at a similar gestation in women who subsequently delivered at term. No significant decrease in levels had occurred by the 4th post-partum day. In view of these findings of unaltered matrix metalloproteinase-1 levels in association with labour, previous reports of raised serum collagenase activity in association with the onset of spontaneous labour, at term and preterm gestation periods, may be due to increased neutrophil collagenase activity.

A pregnant lady with intermittent vaginal bleeding (2007: 3b). Placenta percreta.

Placenta percreta is a potentially life-threatening complication of pregnancy, which is increasing in incidence. Ante-natal diagnosis with ultrasound and magnetic resonance imaging aids the obstetric team in planning further management. We present a case of placenta percreta with imaging and a brief review of the literature.

Use of a confidence scale in reporting postmortem fetal magnetic resonance imaging.

OBJECTIVES: Postmortem magnetic resonance imaging (MRI) may be an alternative to conventional autopsy. However, it is unclear how confident radiologists are in reporting such studies. We sought to determine the confidence with which radiologists report on various fetal organs by developing a scale to express their confidence of normality and abnormality, and to place this in the context of a pathological diagnosis of whether the organ was in fact normal or abnormal. METHODS: Thirty fetuses, aged 16-39 gestational weeks and weighing 61-3270 g, underwent postmortem MRI prior to conventional autopsy. MRI studies were reported by two radiologists with access to the clinical and sonographic history: a neuroradiologist, reporting head and neck, and a pediatric radiologist, reporting thorax, abdomen and pelvis. Radiologists used a scale (0 = definitely abnormal, 100 = definitely normal, 50 = unable to comment) to indicate their confidence of anatomical structures being normal or abnormal, using a checklist. Conventional autopsies were performed by pediatric pathologists blinded to the MRI findings, and these were considered the reference standard. RESULTS: Most normal fetal organs had high scores on postmortem MRI, with median confidence scores above 80. However, the atrioventricular valves, duodenum, bowel rotation and pancreas proved more difficult to assess, with median scores of 50, 60, 60 and 62.5, respectively. Abnormal cardiac atria and ventricles, kidneys, cerebral hemispheres and corpus callosum were always detected with high or moderate degrees of confidence (median scores of 2.5, 5, 0, 0 and 30 respectively). However, in two cases with abnormal cardiac outflow tracts, both cases scored 50. Kappa values, assessing agreement between MRI diagnoses of abnormality and autopsy, were high for the brain (0.83), moderate for the lungs (0.56) and fair for the heart (0.33). CONCLUSIONS: This scoring system represents an attempt to define the confidence of radiologists to report varying degrees of normality and abnormality following z ex-utero fetal MRI. While most fetal anatomy is clearly visualized on postmortem MRI, radiologists may lack confidence reporting such studies and there are particular problems with assessment of some cardiac and gastrointestinal structures, both normal and abnormal.

Doppler ultrasound assessment of fetal and uteroplacental circulations in severe second trimester oligohydramnios.

Doppler blood flow studies in 41 pregnancies with oligohydramnios in the second trimester found abnormal patterns in all 14 pregnancies with intrauterine growth retardation but in only one of nine pregnancies with premature rupture of the membranes, and one of 10 with fetal renal defects. Mixed patterns were found in a heterogeneous group of fetuses with other malformations or intrauterine infection. Unlike previous reports a diagnosis was achieved in all pregnancies, suggesting that Doppler studies should be an integral part of the antenatal investigation in such pregnancies.

Comparison of the Foley catheter and dinoprostone pessary for cervical preparation before second trimester abortion.

The Foley catheter and a 3 mg dinoprostone pessary (Prostin E2) were compared as methods for cervical preparation before second trimester dilatation and evacuation. The catheter was well tolerated and provided significantly greater change in cervical dilatation and improved cervical compliance. The Foley catheter would seem to provide a readily available and efficacious means of cervical preparation.

PIP: A Foley catheter with the balloon inflated above the internal cervical os, and a 3 mg dinoprostone pessary (Prostin E2) were compared for cervical dilatation before early second trimester dilatation and evacuation. Experimental subjects were 21 women given PGE2 and 23 having catheters, comprising all women between 12-16 weeks' gestation presenting consecutively for termination, allocated at random. Cervical preparation was done after an antiseptic swab, 24 hours before surgery. The size 14-Foley catheter was inserted 3-4 cm into the cervix and inflated with 25 ml water; the pessary was inserted into the posterior fornix. Under general anesthesia, dilatation, measured using largest dilators 1st, averaged 10.4 mm compared to 3.2 mm before treatment in the catheter group, but 8.7 in the PG group compared to 3.7. The increase in dilatation was 7.2 mm in the catheter group, and 5.0 in the PG group (p0.003). Cervical compliance, estimated on a scale of 1-5 by the surgeon, averaged 4.4 in the catheter group, and 2.8 in the PG group (p,0.001). 4 women complained of pain after catheters, 1 after PG. There was 1 case of cervical tear and rigid cervix, requiring hysterotomy. In this protocol, the Foley catheter seems to be the most efficient means of dilating the cervix.

Termination of pregnancy following diagnosis of fetal malformation: the need for improved follow-up services.

Eighty parents were offered an emotional support and counseling service following termination of pregnancy for fetal abnormality detected by second trimester ultrasound examination. Twenty couples took up the invitation to talk about their experiences. It was found that these women and their partners were profoundly affected by their decision to terminate the pregnancy. The lack of organized follow-up by existing agencies and the availability of professional support for these parents is a serious deficiency in our prenatal diagnostic services.

PIP: Parents who decide to terminate a pregnancy after an ultrasound diagnosis of structural abnormality in the fetus experience the same feelings of grief and loss as parents feel after a stillbirth or neonatal death, but it is compounded by a feeling of guilt because they themselves decided to terminate the pregnancy. 80 women referred to the Kings College School of Medicine and Dentistry for ultrasound scan between 1984 and 1985 were found to have fetuses with severe structural abnormalities. 20 of them accepted invitations to return for counseling. 18 would have liked more information, and 2 were disturbed by discussion during the scan. After returning to their own hospitals for pregnancy termination, the parents were reinterviewed. All had found the pregnancy termination more traumatic than anticipated. 5 felt that professional support was inadequate. 9 saw the baby and felt that it was important to do so because it confirmed the correctness of their decision, and it gave them a tangible memory of the baby. 16 felt that some burial ceremony should have been observed. 8 of the parents received postabortion follow-up from their general practitioner, and 5 were offered genetic counseling. This study indicated that: 1) There should be rapid referral of patients to a level 3 center; 2) Sympathetic personnel are essential; 3) Adequate pain relief should be available during the procedure; 4) Medical and genetic follow-up should be a matter of course; 5) Medical professionals should be educated about the psychological trauma to be expected in these patients; and 6) A self-help group of couples with similar experiences is helpful.

Utero-placental blood velocity resistance index and umbilical venous pO2, pCO2, pH, lactate and erythroblast count in growth-retarded fetuses.

In 32 pregnancies complicated by intra-uterine growth retardation, umbilical venous blood was sampled by cordocentesis and the utero-placental blood velocity resistance index (RI) was recorded using Doppler ultrasound. Significant correlations were found between the utero-placental RI and fetal hypoxia, hypercapnea, acidosis, hyperlactaemia and erythroblastosis.

Doppler studies in the growth retarded fetus and prediction of neonatal necrotising enterocolitis, haemorrhage, and neonatal morbidity.

In 82 consecutive cases of intrauterine growth retardation managed by established criteria fetal Doppler studies identified 29 fetuses with absence of end diastolic frequencies in the fetal aorta. These same fetuses were significantly more growth retarded (p less than 0.001) and had an earlier gestational age at delivery (p less than 0.001) than those with end diastolic frequencies present. A subgroup of these cases was analysed in more detail to examine the prognostic value of this phenomenon for the neonate. Two groups of neonates of equivalent gestational age and with a birth weight below 2000 g were compared. There were 26 neonates with absent end diastolic frequencies (group 1) and 20 with end diastolic frequencies (group 2) in the fetal aorta. Those in group 1 were more likely to suffer perinatal death (p less than 0.05), necrotising enterocolitis (p less than 0.01), and haemorrhage (p less than 0.05). Only 4 (15%) of the babies in group 1 had an uncomplicated neonatal period compared with 15 (75%) in group 2 (p less than 0.001). The circulatory changes identified in these cases may provide a more sensitive measure of critical fetal compromise than current techniques and thus allow the clinician to deliver the fetus before irreversible tissue damage has occurred.

Prenatal diagnosis from maternal blood: simultaneous immunophenotyping and FISH of fetal nucleated erythrocytes isolated by negative magnetic cell sorting.

Fetal nucleated cells in the maternal circulation constitute a potential source of cells for the non-invasive prenatal diagnosis of fetal genetic abnormalities. We have investigated the use of the Magnetic Activated Cell Sorter (MACS) for enriching fetal nucleated erythrocytes. Mouse monoclonal antibodies specific for CD45 and CD32 were used to deplete leucocytes from maternal blood using MACS sorting, thus enriching for fetal nucleated erythrocytes which do not express either of these antigens. However, significant maternal contamination was present even after MACS enrichment preventing the accurate analysis of fetal cells by interphase fluorescence in situ hybridisation (FISH). To overcome this problem, we used simultaneous immunophenotyping of cells with the mouse antifetal haemoglobin antibody, UCH gamma, combined with FISH analysis using chromosome X and Y specific DNA probes. This approach enables selective FISH analysis of fetal cells within an excess of maternal cells. Furthermore, we have confirmed the potential of the method for clinical practice by a pilot prospective study of fetal sex in women referred for amniocentesis between 13 and 17 weeks of gestation.

Early amniocentesis at 11-14 weeks' gestation for the diagnosis of fetal chromosomal abnormality--a clinical evaluation.

Early amniocentesis between 11 and 14 weeks' gestation was offered to 110 women at risk of a chromosomally abnormal fetus due to maternal age. Four were found to be unsuitable for the procedure, and 106 early amniocenteses were performed. In 102 cases, clear amniotic fluid was obtained with a single tap. There were two dry taps and two bloodstained taps; sampling was repeated in three of these cases before 15 weeks. In the fourth case, placental biopsy was performed at 16 weeks. Thus, we were able to obtain a satisfactory sample in all but three cases (2.8 per cent). Karyotyping of cells harvested from the early amniotic fluid samples was successful in all the 105 cases. Cell culture from the initial samples revealed a normal karyotype in 99 cases, two balanced translocations, two tetraploid karyotypes, and two cases of pseudomosaicism. Of the 105 pregnancies successfully sampled, there have been two losses to date (1.8 per cent). Two further patients presented with premature rupture of membranes, both pregnancies having successful outcomes. Sixty-two babies have delivered to date, with four congenital anomalies. There were no respiratory problems. Twenty-nine pregnancies are continuing without known complications, and details are not yet available on the remaining 12. The results indicate that early amniocentesis may replace the traditional test at 15-17 weeks.

Cytogenetic studies of amniotic fluid taken before the 15th week of pregnancy for earlier prenatal diagnosis: a report of 114 consecutive cases.

One hundred and fourteen samples of amniotic fluid taken before 15 weeks of gestation were cultured for cytogenetic studies. The results of culturing these early amniotic fluid (EAF) samples were compared with the results of culturing 114 standard amniotic fluid (SAF) samples taken after 15 weeks of gestation matched for maternal age and received in the laboratory within the same week. Cell culture was successful in all 114 of the EAF samples and in 111 SAF samples. There was no significant difference in the days to harvesting and days to reporting in the two groups. Three samples of SAF failed to grow and two EAF samples produced tetraploid karyotypes, so that in these five cases amniocentesis had to be repeated. These problems were attributed to toxicity of a fungicide used in the culture medium. Pseudo-mosaicism was noted in two EAF samples and one SAF sample; and maternal cell contamination was noted in one EAF and one SAF sample. Thus, culturing and karyotyping cells harvested from EAF and SAF are similar, indicating that EAF samples from 12-14-week pregnancies could be used for prenatal diagnosis.