Most pregnant women who present for a scheduled first-trimester prenatal visit are well; they do not present with symptoms of miscarriage, and an office ultrasonogram is likely to confirm the presence of fetal cardiac activity. Determining the incidence of miscarriage among such a potentially “low risk” group might be pragmatically very useful for counseling. As far as we are aware, no large prospective study specifically designed to investigate such a group exists. Anecdotally, it seems that conservative estimates are given because it seems almost universal that couples wait until the first trimester is over before they announce their pregnancy.
The overall risk of miscarriage after clinical recognition of pregnancy is 12–15%.1,2 The incidence decreases significantly if fetal cardiac activity has been confirmed. Studies that have examined the incidence of miscarriage after ultrasound evidence of fetal viability have reported estimates between 3% and 12%.3–6 However, heterogeneity in participant profiles and study design exists among these reports. To our knowledge, no previous studies have exclusively investigated women who were asymptomatic. Therefore, the estimates provided by these studies may have been increased by the inclusion of women with a threatened miscarriage, because they are still at higher risk of loss even after viability is demonstrated. Consequently, the estimates given by these prior reports may be an overestimate of the actual risk for asymptomatic, well pregnant women.
The aim of this study was to investigate prospectively the incidence of miscarriage among asymptomatic women presenting for their first prenatal visit between 6 weeks and 11 weeks of gestation where evidence of fetal cardiac activity was obtained by the clinician at the same visit.
MATERIALS AND METHODS
In March 2004, we commenced The Mercy Early Pregnancy Study, a prospective observational study designed to estimate the incidence of miscarriage among asymptomatic women who attend their first prenatal clinic visit between 6 weeks and 11 weeks of gestation. The second aim of the study was to verify biomarkers for miscarriage such as macrophage inhibitory cytokine,7 pregnancy-associated plasma protein-A8 and anandamide hydrolase.9 Given the lower than expected numbers of miscarriage cases (the principle findings of the present study), the biomarker study is currently ongoing. We obtained ethics approval before commencing this study (Mercy Health Human Research and Ethics Committee, study number R03/23).
Mercy Hospital for Women is a public tertiary hospital in Victoria, Australia that manages 5,000–6,000 confinements per year. Women attending antenatal clinic were recruited by research midwives in the waiting room just before their first prenatal visits. Written informed consent was obtained. The inclusion criteria were pregnant women with a singleton pregnancy at 6 weeks (+2 days) to 11 weeks (+6 days) of gestation with no symptoms of miscarriage (such as vaginal bleeding or suprapubic pain) who had ultrasound confirmation of a viable pregnancy. Dates were calculated by crown rump length, and 6 weeks and 2 days was chosen as the earliest gestation for recruitment because it is at this gestation that the fetal heartbeat is expected to be detected reliably by ultrasonography. Those who had a fetus with an embryonic bradycardia noted by the clinician performing the ultrasonography or elected subsequently to have a termination of pregnancy were excluded.
To obtain results that might be the most clinically relevant for counseling, we opted for a pragmatic design. The recruitment point was at the antenatal clinic, not a specialized early pregnancy clinic (which we do not have at our hospital) or an ultrasound department. We recruited women in the waiting room before the clinical consultation so as not to disturb the visit and included women presenting at a range of gestations. Also, we did not use an expert ultrasonographer but rather asked the attending physician to perform the initial ultrasonography. Most of the clinicians were general obstetricians and gynecologists or trainees with basic skills in ultrasonography. No clinicians attending these clinics have formal subspecialty ultrasound qualifications. Also, we did not recruit participants from the Materno-fetal Medicine Unit, which is situated away from the general obstetric clinics. Women were only sent for a formal expert scan if the office ultrasonography was inconclusive (n=42; 6.0%). Fifty-eight women (8.3%) who presented to the prenatal visit came with reports of earlier ultrasonograms ordered by their referring doctors. For these women, an office ultrasonogram was still done at the prenatal visit to confirm viability. However, their agreed gestational age was calculated from the previous ultrasonography if it was a formal expert scan.
We collected baseline details, including maternal age, parity, method of delivery, gestation at delivery, and birth weight. Miscarriage was defined as a pregnancy spontaneously ending before 20 weeks. Our primary outcome was the risk of miscarriage stratified by gestation at presentation. Outcome data were obtained from our computerized birthing outcome system and from medical records. Of 36 women who left our hospital during the antenatal period, we reviewed their records, or called them to determine outcomes. We grouped them in the “nonmiscarriage” group if there was record of an antenatal visit after 20 weeks of gestation. If there was no such record, we included them in the nonmiscarriage group if they had a normal fetal morphology scan on hospital record (done at 18 weeks of gestation or more).
We also obtained further clinical details on the miscarriage cohort, such as the gestation at which symptoms were first noted and the gestation when the diagnosis of miscarriage was made by ultrasonography. All continuous variables were noted to be normally distributed when plotted on a histogram. Therefore, parametric tests were used for continuous variables. Statistical comparisons of categorical data were by χ2 test. Trend in proportion of miscarriages at each gestation age at recruitment was calculated by a nonparametric test for trend across ordered groups.10
Of 697 women with a viable pregnancy, follow-up was obtained on 696, with one pregnancy lost to follow-up. Most (80%) were recruited at 8–10 weeks of gestation. The mean maternal age (±standard deviation) was 31.1 (4.6) years and 51% (359 of 706) were primigravid. Neither of these measures were statistically different in the miscarriage cohort (Table 1). Among the 685 women who did not miscarry, we had complete delivery details (Table 1) in 649 cases, with the remaining 36 confining elsewhere.
Of the 36 women who left our hospital during the antenatal period, all were grouped in the ongoing pregnancy cohort in accordance with the criteria defined in Methods. In 18 cases there was record of normal antenatal visits at more than 20 weeks of gestation. Of the remaining 18 cases, we had records of both a fetal morphology scan at more than 18 weeks of gestation and an entry in the medical records noting that they were moving their antenatal care elsewhere. Although we did not have definitive evidence that this latter group in fact reached 20 weeks of gestation after their normal fetal morphology scan, we consider it unlikely that many will have lost their pregnancy before 20 weeks of gestation.
Of the 696 women, 11 had a miscarriage, providing an overall miscarriage incidence of 1.58% (95% confidence interval [CI] 0–2.5%). Table 2 shows the miscarriage rate stratified by gestation at the prenatal visit. There was a statistically significant trend (P=.001, χ2; test for trend) where risk of losses declined with increasing gestation at presentation. Although losses were relatively high at 6 (completed) weeks of gestation (9.4%, 95% CI 0–19.5), they dropped quickly to be 1.5% (95% CI 0–3.2%) at 8 weeks of gestation and less than 1% from 9 weeks onward.
The relative proportions of women presenting at each gestational week aged younger than or older than 31 years did not vary (two groups per gestational week, 12 groups in total; P=.169, χ2; test for trend). Given this, we compared the risk of miscarriage in the total cohort according to whether they were aged younger than or older than 31 years. The risk of miscarriage in the cohort aged younger than 31 years was 2.6% (8/300), not significantly different from those who were older (0.7%, 3/385; P=.055).
Table 3 provides further clinical details on the 11 women who miscarried. Only one patient received a diagnosis of miscarriage by ultrasonography at less than 10 weeks of gestation and five (45%) were diagnosed at 13 weeks of gestation or more. Two had multiple anomalies detected on ultrasonography. There was one case of fetal death in utero after an amniocentesis, which might have been an iatrogenic loss.
In this study, we found that for asymptomatic women attending a first prenatal visit between 6 weeks and 11 weeks of gestation where fetal viability was confirmed, the subsequent risk of miscarriage is 1.6%. Although the risk was high at 6 weeks of gestation, at 9.4%, it declined rapidly to 1.5% at 8 weeks of gestation, and less than 1% from 9 weeks.
Previous estimates of miscarriage risk after first-trimester ultrasonography showing a live fetus range between 3–12%.2–6 Of studies that provide estimates of losses on the higher end, Tummers et al6 reported fetal death after positive heart activity in 12.2% of singleton pregnancies. However, this was an in vitro fertilization population where the whole cohort had their first scan at approximately 7 weeks of gestation. The largest prospective study published in recent years (excluding the present study) was by Mackrydimas et al,5 who investigated 668 singleton pregnancies with live fetuses. They reported that subsequent miscarriage occurred in 7.5% of pregnancies, with a risk at 8 weeks of gestation of 7.4%, much higher compared with our cohort (1.6%). This study was very different from ours in that it included those who had symptoms of miscarriage and that it seems that the point of recruitment was a single experienced ultrasonographer at an ultrasound department, not an antenatal clinic. This may have introduced a degree of referral bias. Of studies reporting figures at the lower end of estimates, Simpson et al3 found a loss rate of 3.2% among a cohort of 220 women. However, this study was performed 20 years ago where ultrasound scans were probably less sensitive than today. This might have introduced a selection bias at the time of enrolment where women who had a pregnancy with a fetal heartbeat readily detected by today's machines might have been missed.
We have found an estimated risk well below all these previous reports. Our study suggests that those who attend their scheduled first prenatal visit with no symptoms are likely to have an excellent prognosis. Of the minority that miscarry, it would seem from the data that it will often present clinically as a later (second trimester) miscarriage.
Our study has several strengths. It was a large prospective study with very complete follow-up (one patient was lost to follow-up). We used a pragmatic design where the study was embedded into the usual running of an antenatal clinic, not a specialized early pregnancy clinic or an ultrasound department. Our research midwives enrolled women in the waiting room before the medical visit and allowed clinicians to perform their usual consultation, with the exception that we requested that they perform a clinic ultrasound examination to confirm viability. These ultrasound examinations were mostly performed by consultants and trainees without formal subspecialty ultrasound training. Consequently, we believe that our data could be extrapolated generally to health care providers provided that they are able to offer office ultrasonography to confirm viability at that visit.
There obviously needs to be some caution in quoting such a low risk of miscarriage if a women presents with an increased a priori risk such as maternal age,11 assisted reproduction,6 or are increased parity.2 However, it would be difficult to undertake a prospective study of sufficient power to generate tables that can address all these different scenarios.
In conclusion, we have shown that among asymptomatic pregnant women presenting for their first prenatal visit at 8–11 weeks of gestation who have ultrasonography to confirm fetal viability, their risk of subsequent miscarriage 1.5% or less. Our data may be useful as a counseling tool to reassure such women at the end of their first prenatal visit that their risk of loss is already very low.
1. Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189–94.
2. Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. BMJ 1989;299:541–5.
3. Simpson JL, Mills JL, Holmes LB, Ober CL, Aarons J, Jovanovic L, et al. Low fetal loss rates after ultrasound-proved viability in early pregnancy. JAMA 1987;258:2555–7.
4. Condous G, Okaro E, Bourne T. The conservative management of early pregnancy complications: a review of the literature. Ultrasound Obstet Gynecol 2003;22:420–30.
5. Makrydimas G, Sebire NJ, Lolis D, Vlassis N, Nicolaides KH. Fetal loss following ultrasound diagnosis of a live fetus at 6–10 weeks of gestation. Ultrasound Obstet Gynecol 2003;22:368–72.
6. Tummers P, De Sutter P, Dhont M. Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod 2003;18:1720–3.
7. Tong S, Marjono B, Brown DA, Mulvey S, Breit SN, Manuelpillai U, et al. Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet 2004;363:129–30.
8. Tong S, Marjono B, Mulvey S, Wallace EM. Low levels of pregnancy-associated plasma protein-A in asymptomatic women destined for miscarriage. Fertil Steril 2004;82:1468–70.
9. Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agro A. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 2000;355:1326–9.
10. Cuzick J. A Wilcoxon-type test for trend. Stat Med 1985;4:87–90.
11. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320:1708–12.
Figure. No caption available.