primary outcome:
Amniocentesis and chorionic villus sampling for prenatal diagnosis
Tabor 1986 provided the best estimate of an excess pregnancy loss in low‐risk women caused by amniocentesis (3.2% versus 2.3%; RR 1.41, 95% CI 0.99 to 2.00; Analysis 1.1; moderate‐quality evidence), and spontaneous miscarriage (2.1% versus 1.3%; RR 1.60, 95% CI 1.02 to 2.52; Analysis 1.2; high‐quality evidence). However, the confidence intervals around the estimate for pregnancy loss were relatively wide, and were compatible with no or minimal excess risk. It is important to note that 95% CI for absolute risk difference ranged from 0% to 2% for both outcomes. Spontaneous miscarriage after test (pregnancy loss in women who had the test actually performed) was not reported.Compared to an early amniocentesis, mid‐trimester procedure was safer; total pregnancy loss after early amniocentesis was higher (7.6% versus 5.9%; RR 1.29, 95% CI 1.03 to 1.61; Analysis 2.1; high‐quality evidence). There were also more spontaneous miscarriages in the early amniocentesis group (3.6% versus 2.5%; RR 1.41, 95% CI 1.00 to 1.98; Analysis 2.2; moderate‐quality evidence). This was also true for spontaneous miscarriages after test (2.5% versus 0.8%; RR 3.22, 95% CI 1.88 to 5.53; Analysis 2.3).Total pregnancy loss was higher after transcervical CVS compared with amniocentesis (14.5% versus 11.0%; RR 1.40, 95% CI 1.09 to 1.81; women = 6527; studies = four; Analysis 3.1), but these results should be interpreted cautiously. In the transcervical CVS group, the total pregnancy loss varied from 7.3% in the Ammala 1993 (MRC Finland) trial to 19.5% in the Borrell 1999 trial. It is important to note that this was an intention‐to‐treat analysis, which included post‐randomisation, pre‐procedure pregnancy losses. Unfortuntaely, in the Borrell 1999 trial, these losses were extremely high (10.9%) and unbalanced between the two groups. The overall results for total pregnancy loss changed little without Borrell 1999 (RR 1.40, 95% CI 1.00 to 2.06). Interestingly, the statistical test for heterogeneity was significant, despite the fact that the results looked quite similar in terms of the size and direction of the observed differences in total pregnancy loss. The sensitivity analysis suggested that the heterogeneity was caused by the differences between the two largest trials (Canada 1989; Smidt‐Jensen 1993 (Denmark)). The increase in pregnancy loss after transcervical CVS was clear in the Smidt‐Jensen 1993 (Denmark) trial (RR 1.70, 95% CI 1.30 to 2.22), but not in the Canada 1989 trial (1.10, 95% CI 0.92 to 1.30). The results for spontaneous miscarriages (12.9% versus 9.4%; RR 1.5, 95% CI 1.07 to 2.11; studies = three; women = 5506; Analysis 3.2) were consistent with the results for total pregnancy loss described above.There was no clear difference between groups for spontaneous miscarriage after test (pregnancy loss in women who had the test actually performed (RR 1.77, 95% CI 0.28 to 11.00; studies = two; women = 1579; Analysis 3.3).A subgroup of Smidt‐Jensen 1993 (Denmark) compared transabdominal CVS with second trimester amniocentesis and found no clear difference in the total pregnancy loss between the two procedures (6.3% versus 7%; RR 0.90, 95% CI 0.66 to 1.23; studies = one; women = 2234; Analysis 3.1; low‐quality evidence). The same was true for spontaneous miscarriage (3.0% versus 3.9%; RR 0.77, 95% CI 0.49 to 1.21; studies = one; women = 2069; Analysis 3.2; low‐quality evidence).Spontaneous miscarriage after test (pregnancy loss in women who had the test actually performed) was not reported.Two trials with 6503 women presented data for the comparison between CVS performed by any route and mid‐trimester amniocentesis (MRC 1991; Smidt‐Jensen 1993 (Denmark)).Overall pregnancy loss (including termination of pregnancy) was higher after CVS (11.1% versus 8.2%; RR 1.43, 95% CI 1.22 to 1.67; studies = two; women = 6503; Analysis 3.1). Again, an increase in spontaneous miscarriages after CVS was the main contributing factor (RR 3.46, 95% CI 2.21 to 5.42; studies = one; women = 3201; Analysis 3.3. There were more spontaneous miscarriages in the CVS group (7.1% versus 5.0%; RR 1.51, 95% CI 1.23 to 1.85; studies = two; women = 6280; Analysis 3.2).Compared with transabdominal CVS, total pregnancy loss and spontaneous miscarriages were higher after transcervical CVS, but this was due to the excess loss in the transcervical arm of the Smidt‐Jensen 1993 (Denmark) trial. This trial reported total pregnancy loss after transcervical CVS of 12.4% compared with 7.4% after transabdominal CVS. Corresponding figures for spontaneous pregnancy loss were 8.2% and 3%. However, there was no clear difference between groups for total pregnancy loss and miscarriage rate in the other four trials (Bovicelli 1986; Brambati 1991; Tomassini 1988; Jackson 1992). Because of these differences, there was statistical heterogeneity for these two outcomes (I² = 72.3%). When the fixed‐effect model was used to summarise the results for these two outcomes, transcervical CVS was associated with an increase in total pregnancy loss (RR 1.23, 95% CI 1.06 to 1.42) and spontaneous miscarriage (RR 1.75, 95% CI 1.33 to 2.29). However, in the presence of heterogeneity, it was prudent to apply a more conservative random‐effects model. When we applied this statistical model, the differences in pregnancy loss and miscarriage between transabdominal and transcervical CVS were no longer clear (RR 1.68, 95% CI 0.79 to 3.58; Analysis 4.2 for spontaneous miscarriage, and RR 1.16, 95% CI 0.81 to 1.56; Analysis 4.1 for total pregnancy loss; very low‐quality evidence).There were many outcomes with potentially clinically important differences, but the number of events was not large enough to precisely estimate the risks. These were: all known pregnancy loss (including termination of pregnancy; 9.0% versus 7.4%; RR 1.16, 95% CI 0.81 to 1.65; studies = five; women = 7978; Analysis 4.1; very low‐quality evidence), spontaneous miscarriage; 7.9% versus 4.5%; RR 1.68, 95% CI 0.79 to 3.58; studies = four; women = 3384; Analysis 4.2; very low‐quality evidence), spontaneous miscarriage after test (pregnancy loss in women who had the test actually performed; 4.9% versus 3.9%; RR 1.23, 95% CI 0.75 to 2.04; studies = three; women = 1347; Analysis 4.3).In the early amniocentesis group, there were more spontaneous miscarriages; 2.2% versus 1.3%; RR 1.73, 95% CI 1.15 to 2.60; studies = four; women = 5491; Analysis 5.2; moderate‐quality evidence), and more spontaneous miscarriages after test (pregnancy loss in women who had the test actually performed; RR 1.71, 95% CI 1.12 to 2.61; studies = four; women = 5489; Analysis 5.3).There was no clear difference in all known pregnancy loss (including termination of pregnancy; 3.5% versus 3.0%; RR 1.15, 95% CI 0.89 to 1.54; studies = four; women = 5491; Analysis 5.1; low‐quality evidence).There were potentially clinically important differences in all known pregnancy loss (including termination of pregnancy; 0.0% versus 0.9%; RR 0.33, 95% CI 0.01 to 8.02; studies = one; women = 223; Analysis 6.1), spontaneous miscarriage; 0.0% versus 0.9%; RR 0.33, 95% CI 0.01 to 8.02; studies = one; women = 223; Analysis 6.2), spontaneous miscarriage after test (pregnancy loss in women who had the test actually performed; 0.0% versus 0.9%; RR 0.33, 95% CI 0.01 to 8.02; studies = one; women = 223; Analysis 6.3), but the number of events were not large enough to precisely estimate the risks.