Human Reproduction, Vol.30, No.5 pp. 1239 –1245, 2015 Advanced Access publication on March 10, 2015 doi:10.1093/humrep/dev044
ORIGINAL ARTICLE Reproductive epidemiology
Perinatal outcomes in a subsequent pregnancy among women who have experienced recurrent miscarriage: a retrospective cohort study K. Field* and D.J. Murphy Academic Department of Obstetrics & Gynaecology, Trinity College, University of Dublin & Coombe Women & Infants University Hospital, Cork Street, Dublin 8, Republic of Ireland *Correspondence address. Academic Department of Obstetrics & Gynaecology, Trinity College, University of Dublin, Coombe Women & Infants University Hospital, Cork Street, Dublin 8, Republic of Ireland. Tel: +353-1-408-5200; E-mail: fi[email protected]
Submitted on January 5, 2015; resubmitted on February 5, 2015; accepted on February 10, 2015
study question: Is a history of three or more miscarriages associated with adverse perinatal outcomes in a subsequent pregnancy? summary answer: Recurrent miscarriage is associated with an increased risk of adverse perinatal outcomes, including preterm birth, very preterm birth and perinatal death, in a subsequent pregnancy.
what is known already: Published data are conflicting with some studies reporting an increase in adverse perinatal outcomes in association with prior recurrent miscarriage while others report little or no increase. Large-scale population-based studies have been lacking. study design, size, duration: We performed a retrospective cohort study of 30 053 women with a singleton pregnancy who booked for antenatal care and delivery between January 2008 and July 2011. participants/materials, setting, methods: All women who attended a university affiliated hospital in Ireland had a detailed obstetric history taken, recording the outcome of all previous pregnancies. We compared the obstetric and perinatal outcomes of 2030 women (6.8%) who had a history of three or more miscarriages (recurrent miscarriage) with the outcomes of 28 023 women (93.2%) who did not. Logistic regression analyses were performed, adjusting for potential confounding factors.
main results and the role of chance: Women with a history of recurrent miscarriage were more likely to be obese, to have undergone assisted conception, to have had a previous perinatal death, and to be delivered by scheduled Caesarean section. Recurrent miscarriage was associated with an increased incidence of preterm birth (,37 weeks gestation, 8.1 versus 5.5%, adjOR 1.54; 95% CI 1.29 –1.84), very preterm birth (,32 weeks gestation, 2.2 versus 1.2%, adjOR 1.80; 95% CI 1.28 –2.53), and perinatal death (1.2 versus 0.5%, adjOR 2.66; 95% CI 1.70 –4.14). The results were similar for both primary and secondary recurrent miscarriage.
limitations, reasons for caution: This is a retrospective cohort study and while regression analyses adjusted for potential confounding factors, residual confounding may persist. The strict definition of recurrent miscarriage is three consecutive miscarriages and while each woman in the study group had three or more miscarriages, they were only confirmed to be consecutive in the primary RM group. The affected women have not been categorized according to aetiology of recurrent miscarriage and it may be that adverse outcomes differ according to aetiological subgroup. wider implications of the findings: This study highlights the need for specialist obstetric care for women who have had three or more previous miscarriages, particularly in relation to the risk of preterm delivery.
study funding/competing interest(s): There was no specific funding obtained for this study and there are no conflict of interests. Key words: recurrent miscarriage / predictors / perinatal outcomes / cohort study
& The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected]
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Introduction The World Health Organisation has defined miscarriage as the loss of a pregnancy before viability is achieved (WHO International Classification of Disease, 2000). The reported incidence of miscarriage is up to 20% for all clinical pregnancies (WHO, Zinaman et al., 1996). The strict definition of recurrent miscarriage (RM) is three or more consecutive spontaneous miscarriages occurring in the first trimester, with the same biological father (Coulam, 1991). RM is estimated to occur in 1–3% of couples who are trying to conceive (Stirrat, 1990; Carrington et al., 2005). The majority of research in this patient group has addressed risk factors and underlying clinical diagnoses associated with RM. Advanced maternal age, abnormal parental karyotype, endocrine disorders, abnormal uterine pathology, antiphospholipid syndrome and thrombophilic disorders are now well-established causes of recurrent miscarriage (Rai and Regan, 2006). The risk of a subsequent pregnancy resulting in a miscarriage has also been well documented (Clifford et al., 1997). However, there is limited information available for those women who achieve potential viability in a subsequent pregnancy in relation to perinatal outcomes. Studies to date have been based mainly on selected populations with small study numbers (Jivraj et al., 2001; Dempsey et al., 2014). There is a need for evidence-based counselling in relation to perinatal outcomes for women who book for antenatal care with a history of three or more miscarriages. An appropriate plan of care should be scheduled accordingly. The aim of this study was to examine the perinatal outcomes associated with recurrent miscarriage among a large cohort of women booked for antenatal care and delivery within a university teaching hospital setting in Ireland.
Materials and Methods A retrospective cohort study was conducted using the electronic antenatal and delivery records of all women with singleton pregnancies who attended the Coombe Women and Infants University Hospital, between January 2008 and July 2011. This is a large, urban maternity hospital that delivers care to between 8500 and 9000 women each year. The dataset was collated from the electronic record system and included data from the first hospital visit and detailed booking interview up until delivery and post-natal discharge. Neonatal records were also available for all babies up until discharge from hospital. Any woman who attended for antenatal care but who delivered elsewhere was not included in the cohort. The study was limited to women with a singleton pregnancy as the antenatal and peripartum risks associated with multiple pregnancies are well established and are likely to confound the associations of interest. Study participants were subdivided into two groups based on their previous obstetric history. Women with three or more previous miscarriages were categorized into the recurrent miscarriage group regardless of whether or not the miscarriages occurred consecutively and all other women were included in the comparison group. We considered this to be the most accurate approach in case of recall errors when reporting the order of prior pregnancies, not all of which occurred at the booking hospital. Although the hospital has a dedicated recurrent miscarriage clinic, only a small proportion of women had attended the clinic for investigations, therefore we did not sub-classify the recurrent miscarriage women by aetiological groups. Comprehensive records are available routinely for all deliveries of .23 weeks’ gestation or 500 g weight. Information on the following maternal characteristics was extracted from the electronic records: maternal age, marital status, socio-economic group, nationality, planning of pregnancy,
Field and Murphy
gestational age at booking, smoking, alcohol use, history of illicit drug use, and referral to a social worker. Gestational age was estimated from the calculation based on first day of the last menstrual period where the cycle was regular, however, the routine booking ultrasound scan estimate was preferred if the dates were uncertain or there was a discrepancy of .7 days. Socio-economic groups were classified as professional/manager, home duties, non-manual, manual, unemployed and non-classifiable. Nationality was recorded as Irish or non-Irish and was further subdivided into country of origin. Gestational age at booking was banded into three groups: ,12 weeks, 12 – 20 weeks and .20 weeks. Smokers were defined as women who were current smokers at the time of attendance at their first antenatal visit. Current alcohol use was classified according to the woman’s reported use of alcohol at the time of the first visit. Data were also recorded for medical, psychiatric, past obstetric, antenatal and fetal complications. Medical disorders included hypertension requiring treatment, diabetes mellitus (type 1 and type 2), gestational diabetes requiring insulin treatment, respiratory disease including current asthma, cardiac disease other than history of a murmur, haematological conditions including previous venous thromboembolism, inflammatory bowel disease, renal disease other than a single urinary tract infection, autoimmune disease, neurological disease including epilepsy, and serious skin disorders. A detailed psychiatric history was elicited for current or previous depression requiring treatment, previous post-natal depression requiring treatment, and any history of major psychiatric illness or psychosis. The booking blood results were available and included Hepatitis C and HIV status. Body mass index (BMI) was recorded and a BMI ≥ 30.0 was classified as obese and warranted screening for gestational diabetes with a glucose tolerance test at 26 – 28 weeks’ gestation. Assisted conception included ovulation induction, intrauterine insemination or any type of in vitro fertilization. A detailed past obstetric history was recorded. Fetal complications included structural abnormalities, suspected intrauterine growth restriction, oligohydramnios, abnormal umbilical artery Doppler studies, or preterm prelabour rupture of membranes. Antenatal complications included admission for preeclampsia or pregnancy induced hypertension, significant antepartum haemorrhage (sub-classified as placental abruption), placenta praevia, unstable lie, or any infection requiring intravenous antibiotics. The mode of delivery was classified as spontaneous vaginal delivery, operative vaginal delivery or Caesarean section. Caesarean sections were classified as scheduled or emergency. A scheduled Caesarean section was planned electively and booked on the designated consultant’s operating list. Emergency Caesarean sections occurred in labour or with no labour. Perinatal outcome measures included gestational age at delivery, birthweight, infant gender, infant’s Apgar scores at 1 and 5 min, any congenital abnormalities, evidence of aneuploidy (trisomy 15, 18, 21, Turner’s syndrome XO) and admission to the neonatal unit. Preterm birth was defined as the birth of a live baby at ,37 completed weeks gestation. Very preterm birth was defined as the birth of a live baby at ,32 weeks gestation. Preterm birth was further subdivided into those who had a spontaneous preterm birth and those who did not. Small for gestational age (SGA) was defined as a birthweight less than the 10th percentile using individualized birthweight ratios (corrected for maternal height and weight, parity, infant sex, ethnicity and gestation) (http://www.gestation.net). Stillbirth was defined as delivery of a baby showing no signs of life at or after 24 weeks gestation or weighing ≥500 g. Perinatal death included stillbirths and early neonatal deaths (defined as the death of a baby within the first 7 days of life). Congenital anomalies were identified from records of a physical examination of all babies after delivery and from neonatal discharge records.
Statistical analysis The main objective of the study was to determine the perinatal outcomes of women with a history of RM who progressed beyond 23 week’s gestational
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Perinatal outcomes after recurrent miscarriage
age. The analyses were performed using the Statistical Package for Social Sciences (SPSS version 15). Basic descriptive statistics were used to describe maternal characteristics, mode of delivery and perinatal outcomes for women with and without a history of RM. Univariable logistic regression analyses were performed to measure the association between history of RM and baseline characteristics. Further univariable comparisons were performed to measure the association between RM and perinatal outcomes. Multivariable stepwise logistic regression analyses adjusted for baseline differences between the groups. Potential confounding factors included maternal age and BMI (both continuous variables), marital status, socio-economic status, nationality (all categorical), parity, smoking, medical disorders, psychiatric disorders, assisted conception and previous perinatal death (all binary). These factors were chosen because of their known or potential association with RM and adverse perinatal outcome. Results are reported as proportions, odds ratios (OR) and 95% confidence intervals (CI). Subgroup analyses explored perinatal outcomes for women with a history of primary RM (three or more consecutive miscarriages with no prior viable pregnancy) and women with a history of secondary RM (three or more miscarriages and at least one previous viable pregnancy). The validity of the dataset in terms of accuracy and completeness has been reported previously (Murphy and Fahey, 2013; Vaughan et al., 2014). Analyses of the dataset was approved by the Coombe Women and Infants University Hospital research ethics committee (Coombe REC Study No: 22-2009; updated 09-2011). Individual
patient consent was not deemed necessary as the data were collected routinely and anonymized for analysis.
Results Records from a total cohort of 30 053 women with singleton pregnancies attending the Coombe Women and Infants University Hospital between January 2009 and July 2011 were available for analysis. There were a total of 2030 women (6.8%) who gave a history of three or more miscarriages and 28 023 (93.2%) who did not. Of the 2030 women with a history of RM, 382 (18.8%) had primary RM and 1648 (81.2%) had secondary RM.
Descriptive statistics The baseline characteristics of the women are summarized in Table I. Women with a history of RM were less likely to be single (OR 0.51; 95% CI, 0.46 –0.57), to have an unplanned pregnancy (OR 0.60; 95% CI, 0.54– 0.67), or to give a history of illicit drug use (OR 0.74; 95% CI 0.61 –0.91). They were more likely to be older (30 –39 years OR 2.4; 95% CI 2.14 –2.68; .40 years OR 6.25; 95% CI 5.27 –7.41), of Irish nationality (OR 1.32; 95% CI 1.19 –1.47) or have private health insurance (OR 1.89; 95% CI 1.71 –2.09). Medical and obstetric characteristics are
Table I Socio-demographic characteristics of women according to history of recurrent miscarriage. Total n 5 30 053
Recurrent miscarriage n 5 2030 (%)
No recurrent miscarriage n 5 28 023 (%)
Odds ratio (95% confidence intervals)
............................................................................................................................................................................................. Maternal age ,20 years
12 (0.6)
1056 (3.8)
20–29 years
413 (20.3)
10 920 (38.9)
30–39 years
1362 (67.1)
15 019 (53.6)
2.40 (2.14 –2.68)*
243 (12.0)
1028 (3.7)
6.25 (5.27 –7.41)*
483 (23.8)
10 638 (38.0)
0.51 (0.46 –0.57)*
Professional/Manager
575 (28.3)
7697 (27.5)
1.20 (1.07 –1.35)*
Home duties
514 (25.3)
4536 (16.2)
1.82 (1.61 –2.05)*
Non-manual
645 (31.8)
10 355 (37.0)
.40 years Single marital status
0.30 (0.17 –0.54)* 1.00a
Socio-economic group
Manual Unemployed Non-classifiable Irish nationality
1.00a
69 (3.4)
1276 (4.6)
0.87 (0.67 –1.12)
179 (8.8)
2726 (9.7)
1.05 (0.89 –1.25)
47 (2.3)
1408 (5.0)
0.54 (0.40 –0.72)*
1544 (76.1)
19 788 (70.6)
1.32 (1.19 –1.47)* 1.89 (1.71 –2.09)*
Private healthcare
581 (28.6)
4898 (17.5)
Nulliparous
382 (18.8)
11 988 (42.8)
0.31 (0.28 –0.35)*
Unplanned pregnancy
456 (22.5)
9146 (32.6)
0.60 (0.54 –0.67)*
Gestation at booking ,12 weeksa
886 (43.6)
10 773 (38.4)
1.23 (1.12 –1.35)*
12–20 weeks
1021 (50.3)
15 227 (54.3)
1.00a
.20 weeks
114 (5.6)
1850 (6.6)
0.92 (0.75 –1.12)
Current smoker
348 (17.1)
4494 (16.0)
1.08 (0.96 –1.22)
Current alcohol use
109 (5.4)
1745 (6.2)
0.85 (0.70 –1.04)
Illicit drug use (ever)
107 (5.3)
1954 (7.0)
0.74 (0.61 –0.91)*
Social worker referral
37 (1.7)
926 (3.3)
0.54 (0.39 –0.76)*
a Reference category. *P , 0.05.
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Field and Murphy
summarized in Table II. Women with a history of RM were more likely to have a medical disorder (OR 1.28; 95% CI, 1.12 –1.48), a psychiatric history (OR 1.45; 95% CI, 1.29 –1.61), diabetes (OR 1.30; 95% CI, 1.05 –1.61) or obesity (OR 1.57; 95% CI 1.40–1.76). They were nearly twice as likely to have had assisted conception (OR 1.83; 95% CI 1.45– 2.31) and more than twice as likely to have had a previous perinatal death (OR 2.28; 95% CI, 0.50 –0.77). While there was no significant difference in the history of fetal complications, they were more likely to have had antenatal complications (OR 1.22; 95% CI, 1.02 –1.46) or to be delivered by scheduled Caesarean section (OR 1.69; 95% CI, 1.49 – 1.92). There was a significantly higher incidence of placenta praevia in women with a history of RM (OR 2.63 95% CI, 1.70– 4.08) but no significant difference in the incidence of pre-eclampsia or pregnancy induced hypertension.
Perinatal outcomes Women with a history of RM were more likely to deliver preterm (,37 weeks gestation, 8.1 versus 5.5%, OR 1.51; 95% CI 1.28 –1.79) or very preterm (,32 weeks gestation, 2.2 versus 1.2%, OR 1.85; 95% CI 1.35 – 2.55) (Table III). The associations persisted after controlling for potential confounding factors; adjusted OR 1.54 (95% CI 1.29– 1.84) and 1.80 (95% CI 1.28 –2.53) respectively. The proportion of preterm births that resulted from spontaneous preterm labour (,37 weeks) was similar regardless of RM history; 79 of 165 (48%) and 760 of 1553 (49%) respectively. There was a significant difference in the incidence
of perinatal death from all causes (1.2 versus 0.5%, adjOR 2.66; 95% CI, 1.70 –4.14). The perinatal outcomes for women with primary RM were compared with those with secondary RM (Table IV). The incidence of preterm birth (8.6 versus 8.0%, adjOR 1.21; 95% CI 0.79 –1.87) and perinatal death (1.3 versus 1.2%, adjOR 1.15; 95% CI 0.41 –3.28) were very similar. The only significant difference related to NICU admission, which may reflect nulliparity in the primary RM group.
Discussion Summary of main findings This study reports an increased risk of adverse perinatal outcomes in a subsequent pregnancy for women with a history of three or more miscarriages. Adverse outcomes included preterm birth, very preterm birth and perinatal death, and the associations persisted even after known socio-demographic risk factors were accounted for. The increased risk of preterm birth and perinatal death was similar for women with primary and secondary RM, suggesting that any history of three or more miscarriages is relevant, rather than a history of only consecutive pregnancy loss.
Strengths and limitations of the study This study was conducted in a large, urban university affiliated hospital that delivers an average of 9000 women each year from a catchment population of .500 000. There was very little missing data, accurate
Table II Medical and obstetric characteristics of women according to history of recurrent miscarriage. Total n 5 30 053
Recurrent miscarriage n 5 2030 (%)
No recurrent miscarriage n 5 28 023 (%)
Odds ratio (95% confidence intervals)
............................................................................................................................................................................................. Medical disorders (%) Hypothyroid (%) Diabetes (%)a
255 (12.6)
2830 (10.1)
1.28 (1.12 –1.48)*
47 (2.3)
535 (1.9)
1.22 (0.90 –1.65) 1.30 (1.05 –1.61)*
95 (4.7)
1019 (3.6)
417 (20.5)
4252 (15.2)
1.45 (1.29 –1.62)*
36 (1.8)
269 (1.0)
1.86 (1.31 –2.65)*
Body mass index ≥30.0 (%)
429 (21.9)
4085 (14.6)
1.57 (1.40 –1.76)* 0.56 (0.33 –0.96)*
Psychiatric disorders (%) Hepatitis C/HIV (%) Body mass index ,18.0 (%)
14 (0.7)
340 (1.2)
Assisted conception (%)
85 (4.2)
653 (2.3)
1.83 (1.45 –2.31)*
Previous termination (%)
84 (4.1)
1828 (6.5)
0.62 (0.50 –0.77)*
Previous perinatal death (%)
71 (3.5)
439 (1.6)
2.28 (1.77 –2.94)*
Fetal complication (%)
160 (7.9)
2043 (7.3)
1.09 (0.92 –1.29)
Antenatal complication (%)
136 (6.7)
1557 (5.6)
1.22 (1.02 –1.46)*
Pre-eclampsia/PIH (%)b
78 (3.8)
1307 (4.7)
0.82 (0.65 –1.03)
Abruption/APH (%)c
20 (1.0)
183 (0.7)
1.51 (0.95 –2.41)
127 (0.5)
2.63 (1.70 –4.08)*
Placenta praevia (%) Spontaneous vaginal delivery
24 (1.2) 1204 (59.3)
16 275 (58.1)
Operative vaginal delivery
202 (10.0)
4950 (17.7)
0.52 (0.44 –0.60)*
Caesarean section scheduled
342 (16.8)
3002 (10.7)
1.69 (1.49 –1.91)*
Caesarean section emergency
282 (13.9)
3796 (13.5)
1.03 (0.90 –1.17)
a
1.05 (0.96 –1.15)
Diabetes includes pre-existing diabetes and gestational diabetes. PIH pregnancy induced hypertension, not all women delivered for PIH had a completed 24 h urine collection and some may have had pre-eclampsia. c All cases of placental abruption and antepartum haemorrhage requiring delivery. *P , 0.05. b
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Perinatal outcomes after recurrent miscarriage
Table III Perinatal outcomes according to history of recurrent miscarriage. Recurrent miscarriage n 5 2030 (%)
Not recurrent miscarriage n 5 28 023 (%)
Adjusted ORa (95% CI)
Difference in means (95% CI) Odds ratio (95% CI)
............................................................................................................................................................................................. Gestational age (weeks), mean (SD)
39.1 (2.3)
39.6 (2.0)
20.5 (20.6 to 20.4)
–
Birthweight (grams), mean (SD)
3417 (652)
3442 (583)
225 (252 to 2)
–
165 (8.1)
1551 (5.5)
1.51 (1.28 to 1.79)*
1.54 (1.29 to 1.84)*
Preterm birth ,37 weeks (%) Very preterm birth ,32 weeks (%) Birthweight ,10th centile (%) Male infant (%)
44 (2.2)
331 (1.2)
1.85 (1.35 to 2.55)*
1.80 (1.28 to 2.53)*
263 (13.0)
3481 (12.4)
1.05 (0.92 to 1.20)
1.07 (0.93 to 1.23)
1034 (50.9)
14 449 (51.6)
0.98 (0.89 to 1.07)
0.98 (0.89 to 1.07)
1.68 (1.12 to 2.53)*
1.54 (0.98 to 2.42)
Apgar score ,7 at 5 min (%)
26 (1.3)
215 (0.8)
Admitted to neonatal unit (%)
307 (15.1)
3940 (14.1)
1.09 (0.96 to 1.24)
1.13 (0.99 to 1.30)
14 (0.7)
204 (0.7)
0.95 (0.55 to 1.63)
0.84 (0.47 to 1.48)
4 (0.2)
49 (0.2)
1.13 (0.41 to 3.13)
0.72 (0.26 to 2.03)
25 (1.2)
154 (0.5)
2.26 (1.48 to 3.45)*
2.66 (1.70 to 4.14)*
Congenital abnormality (%) Aneuploidy (Trisomy/XO) (%) Perinatal death (%)
a Adjusted for maternal age, marital status, SE group, parity, medical disorders, psychiatric disorders, BMI, assisted conception, previous perinatal death. *P , 0.05.
Table IV Perinatal outcomes according to history of primary or secondary recurrent miscarriage. Primary recurrent miscarriage n 5 382 (%)
Secondary recurrent miscarriage n 5 1648(%)
Difference in means (95% CI) Odds ratio (95% CI)
Difference in means (95% CI) Adjusted ORa (95% CI)
............................................................................................................................................................................................. Gestational age (weeks), mean (SD)
39.2 (2.6)
39.1 (2.3)
0.1 (20.2 to 0.4)
–
Birthweight (grams), mean (SD)
3324 (635)
3438 (654)
2114 (2186 to 242)
–
Preterm birth ,37 weeks (%)
33 (8.6)
132 (8.0)
1.09 (0.73 to 1.62)
1.21 (0.79 to 1.87)
Very preterm birth ,32 weeks (%)
12 (3.1)
32 (1.9)
1.64 (0.84 to 3.21)
1.75 (0.83 to 3.69) 0.82 (0.57 to 1.19)
Birthweight ,10th centile (%)
42 (11.0)
221 (13.4)
0.80 (0.56 to 1.13)
197 (51.6)
837 (50.8)
1.03 (0.83 to 1.29)
1.00 (0.81 to 1.27)
Apgar score ,7 at 5 min (%)
7 (1.8)
19 (1.2)
1.61 (0.67 to 3.86)
1.24 (0.45 to 3.39)
Admitted to neonatal unit (%)
79 (20.7)
228 (13.8)
1.62 (1.22 to 2.16)*
1.76 (1.29 to 2.39)*
Congenital abnormality (%)
3 (0.8)
11 (0.7)
1.18 (0.33 to 4.24)
0.97 (0.24 to 3.98)
Aneuploidy (Trisomy/XO) (%)
0 (0.0)
4 (0.2)
Perinatal death (%)
5 (1.3)
20 (1.2)
Male infant (%)
– 1.08 (0.40 to 2.90)
– 1.15 (0.41 to 3.28)
a Adjusted for maternal age, marital status, SE group, medical disorders, psychiatric disorders, BMI, assisted conception, previous perinatal death. *P , 0.05.
dating of each pregnancy, and routine ascertainment of the perinatal outcomes of interest. The large sample size and detailed dataset allowed us to perform robust analyses of less common outcomes including very preterm birth and perinatal death. This is a retrospective cohort study and while regression analyses adjusted for potential confounding factors, residual confounding may persist. The strict definition of recurrent miscarriage is three consecutive miscarriages and while each woman in the study group had three or more miscarriages, these were not necessarily consecutive or with the same partner. However, adverse perinatal outcomes were very similar for both primary and secondary RM. The affected women had not been categorized according to aetiology of recurrent miscarriage and it may be that adverse outcomes
differ according to aetiological subgroup. However, many women with a history of three or more miscarriages book for antenatal care without prior assessment at a recurrent miscarriage clinic, and of those who have been assessed, approximately half will be diagnosed with unexplained RM (Clifford et al., 1994).
Comparison with existing literature The prevalence of RM as defined within our cohort was 6.8% with almost one in five women experiencing primary RM. This equates with an overall population prevalence of 1.3% for primary RM, in keeping with other studies (Stirrat, 1990; Carrington et al., 2005). Some studies have
1244 defined RM as two or more consecutive spontaneous miscarriages (Bhattacharya et al., 2010; Bashiri et al., 2012) and one study reported an association with placental abruption, hypertensive disorders and Caesarean section (Sheiner et al., 2005). Women with two miscarriages were included in the comparison group for our analyses, which if anything would result in an underestimation of the true association between recurrent RM and adverse perinatal outcome. There was clear evidence of an association between RM and obesity in keeping with the findings of others (Metwally et al., 2010; Lo et al., 2012). While we did not look specifically at the association between increased BMI and adverse perinatal outcome, this association has been well documented (Rosenberg et al., 2003; Cedergren, 2004). Many studies have investigated the relationship between hypothyroidism and recurrent miscarriage. Similar to the study by Bernardi et al. (2013), we did not find any strong evidence to suggest that there is a difference in the subsequent pregnancy outcome of women with a history of RM and hypothyroidism. The association between RM and assisted conception is also well recognized and, as with scheduled Caesarean section, it is difficult to differentiate the impact of cause and effect. Unlike other studies, we did not find a significant association between RM and pre-eclampsia or placental abruption (Sheiner et al., 2005; Trogstad et al., 2009). The association between RM and placenta praevia is striking and may reflect repeated surgical evacuation of retained products of conception among this group. The literature to date has focused mainly on whether or not a pregnancy is achieved following RM and the effectiveness of therapeutic options, taking account of specific aetiological subgroups and idiopathic RM (Tang and Quenby, 2010; Duckitt and Qureshi, 2011). The data on perinatal outcomes are more limited. Some studies have reported similar findings to ours with an association between RM and preterm delivery, perinatal death and delivery by Caesarean section, however the numbers included were small with limited attention to confounding factors (Jivraj et al., 2001). Dempsey et al. (2014) reported no significant increase in the risk of growth restriction, delivery by Caesarean section or perinatal death in a prospective cohort of women with unexplained RM, however only 42 women were studied. Our study showed similar perinatal outcomes for women who experienced primary RM and secondary RM, apart from an increase in the number of infants admitted to the neonatal unit following primary RM. This contrasts with a study by Shapira et al. (2012) who reported a significantly higher incidence of preterm birth in the primary RM group, based on a study size of 420 women. In 2009, Van Oppenraaij et al. published a review of the literature on adverse obstetric outcomes after early pregnancy complications, including recurrent miscarriage. They focused on the obstetric and perinatal outcomes following RM and found only one study that distinguished between the underlying cause for the RM and idiopathic RM. They concluded that larger studies addressing the risk of adverse perinatal outcome in women with idiopathic RM were needed. While our study did not distinguish between idiopathic RM and those with an underlying cause, our analyses adjusted for known preexisting medical disorders.
Implications for practice This study highlights the need for specialist obstetric care for women who have had three or more previous miscarriages, regardless of whether or not they are consecutive. Factors associated with RM included obesity,
Field and Murphy
assisted conception and pre-existing medical disorders. Pre-pregnancy planning should target weight loss and optimization of health and wellbeing prior to attempting pregnancy. The associations between RM and prematurity, perinatal death and scheduled Caesarean section are likely to be related. A management schedule addressing these risks should be put in place with maternal and fetal monitoring that addresses common underlying pathologies, including fetal growth restriction, placental dysfunction, pre-eclampsia and spontaneous preterm labour.
Conclusions This study provides important information for counselling women with a history of three or more miscarriages. These women should be offered specialist obstetric care from the start of pregnancy with an emphasis on strategies to manage the increased risk of preterm birth and perinatal death.
Acknowledgements We would like to thank the midwives and other staff members who collect the data with great care and the IT and B Cleary who helped with data extraction and coding.
Authors’ roles K.F. interpreted the data and drafted the manuscript. D.J.M. had the idea for the study, performed the analyses, interpreted the data and assisted with drafting of the manuscript. D.J.M. is the guarantor.
Funding No external funding was either sought or obtained for this study.
Conflict of interest None declared.
References Bashiri A, Ratzon R, Amar S, Serjienko R, Mazor M, Shoham-Vardi I. Two vs. three or more primary recurrent pregnancy losses - are there any differences in epidemiologic characteristics and index pregnancy outcome? J Perinat Med 2012;40:365– 371. Bernardi LA, Cohen RN, Stephenson MD. Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss. Fertil Steril 2013;101:1326 – 1331. Bhattacharya S, Townend J, Bhattacharya S. Recurrent miscarriage: are three miscarriages one too many? Analysis of a Scottish population-based database of 151,021 pregnancies. Eur J Obstet Gynecol Reprod Biol 2010; 150:24– 27. Carrington B, Sacks G, Regan L. Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 2005;17:591– 597. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol 2004;103:219 – 224. Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994;9:1328 – 1332. Clifford K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 1997;12:387– 389.
Perinatal outcomes after recurrent miscarriage
Coulam CB. Epidemiology of recurrent spontaneous abortion. Am J Reprod Immunol 1991;26:23 – 27. Dempsey MA, Flood K, Burke N, Fletcher P, Kirkham C, Geary MP, Malone FD. Perinatal outcomes of women with a prior history of unexplained recurrent miscarriage. J Matern Fetal Neonatal Med 2014;4:1–4. Duckitt K, Qureshi A. Recurrent miscarriage. Clin Evid 2011;02:1409. Jivraj S, Anstie B, Cheong YC, Fairlie FM, Laird SM, Li TC. Obstetric and neonatal outcome in women with a history of recurrent miscarriage: a cohort study. Hum Repod 2001;16:102 – 106. Lo W, Rai R, Hameed A, Brailsford SR, Al-Ghamdi AA, Regan L. The effect of body mass index on the outcome of pregnancy in women with recurrent miscarriage. J Family Community Med 2012;19:167 – 171. Metwally M, Saravelos SH, Ledger WL, Li TC. Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril 2010; 94:290– 295. Murphy DJ, Fahey T. A retrospective cohort study of mode of delivery among public and private patients in an integrated maternity hospital setting. BMJ Open 2013;3:e003865. Rai R, Regan L. Recurrent miscarriage. Lancet 2006;368:601– 611. Rosenberg TJ, Garbers S, Chavkin W, Chiasson MA. Prepregnancy weight and adverse perinatal outcomes in an ethnically diverse population. Obstet Gynecol 2003;102:11022 –11027. Shapira E, Ratzon R, Shoham-Vardi I, Serjienko R, Bashiri A. Primary vs. secondary recurrent pregnancy loss—epidemiological characteristics, etiology, and next pregnancy outcome. J Perinat Med 2012;40:389 – 396.
1245 Sheiner E, Levy A, Katz M, Mazor M. Pregnancy outcome following recurrent spontaneous abortions. Eur J Obstet Gynecol Reprod Biol 2005;118:61 – 65. Stirrat GM. Recurrent miscarriage: definition and epidemiology. Lancet, 1990; 336:673– 675. Tang AW, Quenby S. Recent thoughts on management and prevention of recurrent early pregnancy loss. Curr Opin Obstet Gynecol 2010; 22:446– 451. Trogstad L, Magnus P, Moffett A, Stoltenberg C. The effect of recurrent miscarriage and infertility on the risk of pre-eclampsia. BJOG 2009; 116:108– 113. Van Oppenraaij RHF, Jauniaux E, Christiansen OB, Horcajadas JA, Farquharson RG, Exalto N, on behalf of the ESHRE Special Interest Group for Early Pregnancy (SIGEP). Predicting adverse obstetric outcome after early pregnancy events and complications: a review. Hum Reprod Update 2009;15:409 – 421. Vaughan D, Cleary B, Murphy DJ. Delivery outcomes for nulliparous women at the extremes of maternal age—a cohort study. BJOG 2014; 121:261– 268. World Health Organization Regional office for Europe. Definitions and Indicators in Family Planning, Maternal and Child Health and Reproductive Health. WHO Regional Strategy on Sexual and Reproductive Health. Copenhagen: WHO Regional Office for Europe, Denmark, 2000. Zinaman MJ, Clegg DE, Brown CC, O’Connor J, Selevan SG. Estimates of human fertility and pregnancy loss. Fertil Steril 1996;65:503– 509.
ORIGINAL ARTICLE Reproductive epidemiology
Perinatal outcomes in a subsequent pregnancy among women who have experienced recurrent miscarriage: a retrospective cohort study K. Field* and D.J. Murphy Academic Department of Obstetrics & Gynaecology, Trinity College, University of Dublin & Coombe Women & Infants University Hospital, Cork Street, Dublin 8, Republic of Ireland *Correspondence address. Academic Department of Obstetrics & Gynaecology, Trinity College, University of Dublin, Coombe Women & Infants University Hospital, Cork Street, Dublin 8, Republic of Ireland. Tel: +353-1-408-5200; E-mail: fi[email protected]
Submitted on January 5, 2015; resubmitted on February 5, 2015; accepted on February 10, 2015
study question: Is a history of three or more miscarriages associated with adverse perinatal outcomes in a subsequent pregnancy? summary answer: Recurrent miscarriage is associated with an increased risk of adverse perinatal outcomes, including preterm birth, very preterm birth and perinatal death, in a subsequent pregnancy.
what is known already: Published data are conflicting with some studies reporting an increase in adverse perinatal outcomes in association with prior recurrent miscarriage while others report little or no increase. Large-scale population-based studies have been lacking. study design, size, duration: We performed a retrospective cohort study of 30 053 women with a singleton pregnancy who booked for antenatal care and delivery between January 2008 and July 2011. participants/materials, setting, methods: All women who attended a university affiliated hospital in Ireland had a detailed obstetric history taken, recording the outcome of all previous pregnancies. We compared the obstetric and perinatal outcomes of 2030 women (6.8%) who had a history of three or more miscarriages (recurrent miscarriage) with the outcomes of 28 023 women (93.2%) who did not. Logistic regression analyses were performed, adjusting for potential confounding factors.
main results and the role of chance: Women with a history of recurrent miscarriage were more likely to be obese, to have undergone assisted conception, to have had a previous perinatal death, and to be delivered by scheduled Caesarean section. Recurrent miscarriage was associated with an increased incidence of preterm birth (,37 weeks gestation, 8.1 versus 5.5%, adjOR 1.54; 95% CI 1.29 –1.84), very preterm birth (,32 weeks gestation, 2.2 versus 1.2%, adjOR 1.80; 95% CI 1.28 –2.53), and perinatal death (1.2 versus 0.5%, adjOR 2.66; 95% CI 1.70 –4.14). The results were similar for both primary and secondary recurrent miscarriage.
limitations, reasons for caution: This is a retrospective cohort study and while regression analyses adjusted for potential confounding factors, residual confounding may persist. The strict definition of recurrent miscarriage is three consecutive miscarriages and while each woman in the study group had three or more miscarriages, they were only confirmed to be consecutive in the primary RM group. The affected women have not been categorized according to aetiology of recurrent miscarriage and it may be that adverse outcomes differ according to aetiological subgroup. wider implications of the findings: This study highlights the need for specialist obstetric care for women who have had three or more previous miscarriages, particularly in relation to the risk of preterm delivery.
study funding/competing interest(s): There was no specific funding obtained for this study and there are no conflict of interests. Key words: recurrent miscarriage / predictors / perinatal outcomes / cohort study
& The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected]
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Introduction The World Health Organisation has defined miscarriage as the loss of a pregnancy before viability is achieved (WHO International Classification of Disease, 2000). The reported incidence of miscarriage is up to 20% for all clinical pregnancies (WHO, Zinaman et al., 1996). The strict definition of recurrent miscarriage (RM) is three or more consecutive spontaneous miscarriages occurring in the first trimester, with the same biological father (Coulam, 1991). RM is estimated to occur in 1–3% of couples who are trying to conceive (Stirrat, 1990; Carrington et al., 2005). The majority of research in this patient group has addressed risk factors and underlying clinical diagnoses associated with RM. Advanced maternal age, abnormal parental karyotype, endocrine disorders, abnormal uterine pathology, antiphospholipid syndrome and thrombophilic disorders are now well-established causes of recurrent miscarriage (Rai and Regan, 2006). The risk of a subsequent pregnancy resulting in a miscarriage has also been well documented (Clifford et al., 1997). However, there is limited information available for those women who achieve potential viability in a subsequent pregnancy in relation to perinatal outcomes. Studies to date have been based mainly on selected populations with small study numbers (Jivraj et al., 2001; Dempsey et al., 2014). There is a need for evidence-based counselling in relation to perinatal outcomes for women who book for antenatal care with a history of three or more miscarriages. An appropriate plan of care should be scheduled accordingly. The aim of this study was to examine the perinatal outcomes associated with recurrent miscarriage among a large cohort of women booked for antenatal care and delivery within a university teaching hospital setting in Ireland.
Materials and Methods A retrospective cohort study was conducted using the electronic antenatal and delivery records of all women with singleton pregnancies who attended the Coombe Women and Infants University Hospital, between January 2008 and July 2011. This is a large, urban maternity hospital that delivers care to between 8500 and 9000 women each year. The dataset was collated from the electronic record system and included data from the first hospital visit and detailed booking interview up until delivery and post-natal discharge. Neonatal records were also available for all babies up until discharge from hospital. Any woman who attended for antenatal care but who delivered elsewhere was not included in the cohort. The study was limited to women with a singleton pregnancy as the antenatal and peripartum risks associated with multiple pregnancies are well established and are likely to confound the associations of interest. Study participants were subdivided into two groups based on their previous obstetric history. Women with three or more previous miscarriages were categorized into the recurrent miscarriage group regardless of whether or not the miscarriages occurred consecutively and all other women were included in the comparison group. We considered this to be the most accurate approach in case of recall errors when reporting the order of prior pregnancies, not all of which occurred at the booking hospital. Although the hospital has a dedicated recurrent miscarriage clinic, only a small proportion of women had attended the clinic for investigations, therefore we did not sub-classify the recurrent miscarriage women by aetiological groups. Comprehensive records are available routinely for all deliveries of .23 weeks’ gestation or 500 g weight. Information on the following maternal characteristics was extracted from the electronic records: maternal age, marital status, socio-economic group, nationality, planning of pregnancy,
Field and Murphy
gestational age at booking, smoking, alcohol use, history of illicit drug use, and referral to a social worker. Gestational age was estimated from the calculation based on first day of the last menstrual period where the cycle was regular, however, the routine booking ultrasound scan estimate was preferred if the dates were uncertain or there was a discrepancy of .7 days. Socio-economic groups were classified as professional/manager, home duties, non-manual, manual, unemployed and non-classifiable. Nationality was recorded as Irish or non-Irish and was further subdivided into country of origin. Gestational age at booking was banded into three groups: ,12 weeks, 12 – 20 weeks and .20 weeks. Smokers were defined as women who were current smokers at the time of attendance at their first antenatal visit. Current alcohol use was classified according to the woman’s reported use of alcohol at the time of the first visit. Data were also recorded for medical, psychiatric, past obstetric, antenatal and fetal complications. Medical disorders included hypertension requiring treatment, diabetes mellitus (type 1 and type 2), gestational diabetes requiring insulin treatment, respiratory disease including current asthma, cardiac disease other than history of a murmur, haematological conditions including previous venous thromboembolism, inflammatory bowel disease, renal disease other than a single urinary tract infection, autoimmune disease, neurological disease including epilepsy, and serious skin disorders. A detailed psychiatric history was elicited for current or previous depression requiring treatment, previous post-natal depression requiring treatment, and any history of major psychiatric illness or psychosis. The booking blood results were available and included Hepatitis C and HIV status. Body mass index (BMI) was recorded and a BMI ≥ 30.0 was classified as obese and warranted screening for gestational diabetes with a glucose tolerance test at 26 – 28 weeks’ gestation. Assisted conception included ovulation induction, intrauterine insemination or any type of in vitro fertilization. A detailed past obstetric history was recorded. Fetal complications included structural abnormalities, suspected intrauterine growth restriction, oligohydramnios, abnormal umbilical artery Doppler studies, or preterm prelabour rupture of membranes. Antenatal complications included admission for preeclampsia or pregnancy induced hypertension, significant antepartum haemorrhage (sub-classified as placental abruption), placenta praevia, unstable lie, or any infection requiring intravenous antibiotics. The mode of delivery was classified as spontaneous vaginal delivery, operative vaginal delivery or Caesarean section. Caesarean sections were classified as scheduled or emergency. A scheduled Caesarean section was planned electively and booked on the designated consultant’s operating list. Emergency Caesarean sections occurred in labour or with no labour. Perinatal outcome measures included gestational age at delivery, birthweight, infant gender, infant’s Apgar scores at 1 and 5 min, any congenital abnormalities, evidence of aneuploidy (trisomy 15, 18, 21, Turner’s syndrome XO) and admission to the neonatal unit. Preterm birth was defined as the birth of a live baby at ,37 completed weeks gestation. Very preterm birth was defined as the birth of a live baby at ,32 weeks gestation. Preterm birth was further subdivided into those who had a spontaneous preterm birth and those who did not. Small for gestational age (SGA) was defined as a birthweight less than the 10th percentile using individualized birthweight ratios (corrected for maternal height and weight, parity, infant sex, ethnicity and gestation) (http://www.gestation.net). Stillbirth was defined as delivery of a baby showing no signs of life at or after 24 weeks gestation or weighing ≥500 g. Perinatal death included stillbirths and early neonatal deaths (defined as the death of a baby within the first 7 days of life). Congenital anomalies were identified from records of a physical examination of all babies after delivery and from neonatal discharge records.
Statistical analysis The main objective of the study was to determine the perinatal outcomes of women with a history of RM who progressed beyond 23 week’s gestational
1241
Perinatal outcomes after recurrent miscarriage
age. The analyses were performed using the Statistical Package for Social Sciences (SPSS version 15). Basic descriptive statistics were used to describe maternal characteristics, mode of delivery and perinatal outcomes for women with and without a history of RM. Univariable logistic regression analyses were performed to measure the association between history of RM and baseline characteristics. Further univariable comparisons were performed to measure the association between RM and perinatal outcomes. Multivariable stepwise logistic regression analyses adjusted for baseline differences between the groups. Potential confounding factors included maternal age and BMI (both continuous variables), marital status, socio-economic status, nationality (all categorical), parity, smoking, medical disorders, psychiatric disorders, assisted conception and previous perinatal death (all binary). These factors were chosen because of their known or potential association with RM and adverse perinatal outcome. Results are reported as proportions, odds ratios (OR) and 95% confidence intervals (CI). Subgroup analyses explored perinatal outcomes for women with a history of primary RM (three or more consecutive miscarriages with no prior viable pregnancy) and women with a history of secondary RM (three or more miscarriages and at least one previous viable pregnancy). The validity of the dataset in terms of accuracy and completeness has been reported previously (Murphy and Fahey, 2013; Vaughan et al., 2014). Analyses of the dataset was approved by the Coombe Women and Infants University Hospital research ethics committee (Coombe REC Study No: 22-2009; updated 09-2011). Individual
patient consent was not deemed necessary as the data were collected routinely and anonymized for analysis.
Results Records from a total cohort of 30 053 women with singleton pregnancies attending the Coombe Women and Infants University Hospital between January 2009 and July 2011 were available for analysis. There were a total of 2030 women (6.8%) who gave a history of three or more miscarriages and 28 023 (93.2%) who did not. Of the 2030 women with a history of RM, 382 (18.8%) had primary RM and 1648 (81.2%) had secondary RM.
Descriptive statistics The baseline characteristics of the women are summarized in Table I. Women with a history of RM were less likely to be single (OR 0.51; 95% CI, 0.46 –0.57), to have an unplanned pregnancy (OR 0.60; 95% CI, 0.54– 0.67), or to give a history of illicit drug use (OR 0.74; 95% CI 0.61 –0.91). They were more likely to be older (30 –39 years OR 2.4; 95% CI 2.14 –2.68; .40 years OR 6.25; 95% CI 5.27 –7.41), of Irish nationality (OR 1.32; 95% CI 1.19 –1.47) or have private health insurance (OR 1.89; 95% CI 1.71 –2.09). Medical and obstetric characteristics are
Table I Socio-demographic characteristics of women according to history of recurrent miscarriage. Total n 5 30 053
Recurrent miscarriage n 5 2030 (%)
No recurrent miscarriage n 5 28 023 (%)
Odds ratio (95% confidence intervals)
............................................................................................................................................................................................. Maternal age ,20 years
12 (0.6)
1056 (3.8)
20–29 years
413 (20.3)
10 920 (38.9)
30–39 years
1362 (67.1)
15 019 (53.6)
2.40 (2.14 –2.68)*
243 (12.0)
1028 (3.7)
6.25 (5.27 –7.41)*
483 (23.8)
10 638 (38.0)
0.51 (0.46 –0.57)*
Professional/Manager
575 (28.3)
7697 (27.5)
1.20 (1.07 –1.35)*
Home duties
514 (25.3)
4536 (16.2)
1.82 (1.61 –2.05)*
Non-manual
645 (31.8)
10 355 (37.0)
.40 years Single marital status
0.30 (0.17 –0.54)* 1.00a
Socio-economic group
Manual Unemployed Non-classifiable Irish nationality
1.00a
69 (3.4)
1276 (4.6)
0.87 (0.67 –1.12)
179 (8.8)
2726 (9.7)
1.05 (0.89 –1.25)
47 (2.3)
1408 (5.0)
0.54 (0.40 –0.72)*
1544 (76.1)
19 788 (70.6)
1.32 (1.19 –1.47)* 1.89 (1.71 –2.09)*
Private healthcare
581 (28.6)
4898 (17.5)
Nulliparous
382 (18.8)
11 988 (42.8)
0.31 (0.28 –0.35)*
Unplanned pregnancy
456 (22.5)
9146 (32.6)
0.60 (0.54 –0.67)*
Gestation at booking ,12 weeksa
886 (43.6)
10 773 (38.4)
1.23 (1.12 –1.35)*
12–20 weeks
1021 (50.3)
15 227 (54.3)
1.00a
.20 weeks
114 (5.6)
1850 (6.6)
0.92 (0.75 –1.12)
Current smoker
348 (17.1)
4494 (16.0)
1.08 (0.96 –1.22)
Current alcohol use
109 (5.4)
1745 (6.2)
0.85 (0.70 –1.04)
Illicit drug use (ever)
107 (5.3)
1954 (7.0)
0.74 (0.61 –0.91)*
Social worker referral
37 (1.7)
926 (3.3)
0.54 (0.39 –0.76)*
a Reference category. *P , 0.05.
1242
Field and Murphy
summarized in Table II. Women with a history of RM were more likely to have a medical disorder (OR 1.28; 95% CI, 1.12 –1.48), a psychiatric history (OR 1.45; 95% CI, 1.29 –1.61), diabetes (OR 1.30; 95% CI, 1.05 –1.61) or obesity (OR 1.57; 95% CI 1.40–1.76). They were nearly twice as likely to have had assisted conception (OR 1.83; 95% CI 1.45– 2.31) and more than twice as likely to have had a previous perinatal death (OR 2.28; 95% CI, 0.50 –0.77). While there was no significant difference in the history of fetal complications, they were more likely to have had antenatal complications (OR 1.22; 95% CI, 1.02 –1.46) or to be delivered by scheduled Caesarean section (OR 1.69; 95% CI, 1.49 – 1.92). There was a significantly higher incidence of placenta praevia in women with a history of RM (OR 2.63 95% CI, 1.70– 4.08) but no significant difference in the incidence of pre-eclampsia or pregnancy induced hypertension.
Perinatal outcomes Women with a history of RM were more likely to deliver preterm (,37 weeks gestation, 8.1 versus 5.5%, OR 1.51; 95% CI 1.28 –1.79) or very preterm (,32 weeks gestation, 2.2 versus 1.2%, OR 1.85; 95% CI 1.35 – 2.55) (Table III). The associations persisted after controlling for potential confounding factors; adjusted OR 1.54 (95% CI 1.29– 1.84) and 1.80 (95% CI 1.28 –2.53) respectively. The proportion of preterm births that resulted from spontaneous preterm labour (,37 weeks) was similar regardless of RM history; 79 of 165 (48%) and 760 of 1553 (49%) respectively. There was a significant difference in the incidence
of perinatal death from all causes (1.2 versus 0.5%, adjOR 2.66; 95% CI, 1.70 –4.14). The perinatal outcomes for women with primary RM were compared with those with secondary RM (Table IV). The incidence of preterm birth (8.6 versus 8.0%, adjOR 1.21; 95% CI 0.79 –1.87) and perinatal death (1.3 versus 1.2%, adjOR 1.15; 95% CI 0.41 –3.28) were very similar. The only significant difference related to NICU admission, which may reflect nulliparity in the primary RM group.
Discussion Summary of main findings This study reports an increased risk of adverse perinatal outcomes in a subsequent pregnancy for women with a history of three or more miscarriages. Adverse outcomes included preterm birth, very preterm birth and perinatal death, and the associations persisted even after known socio-demographic risk factors were accounted for. The increased risk of preterm birth and perinatal death was similar for women with primary and secondary RM, suggesting that any history of three or more miscarriages is relevant, rather than a history of only consecutive pregnancy loss.
Strengths and limitations of the study This study was conducted in a large, urban university affiliated hospital that delivers an average of 9000 women each year from a catchment population of .500 000. There was very little missing data, accurate
Table II Medical and obstetric characteristics of women according to history of recurrent miscarriage. Total n 5 30 053
Recurrent miscarriage n 5 2030 (%)
No recurrent miscarriage n 5 28 023 (%)
Odds ratio (95% confidence intervals)
............................................................................................................................................................................................. Medical disorders (%) Hypothyroid (%) Diabetes (%)a
255 (12.6)
2830 (10.1)
1.28 (1.12 –1.48)*
47 (2.3)
535 (1.9)
1.22 (0.90 –1.65) 1.30 (1.05 –1.61)*
95 (4.7)
1019 (3.6)
417 (20.5)
4252 (15.2)
1.45 (1.29 –1.62)*
36 (1.8)
269 (1.0)
1.86 (1.31 –2.65)*
Body mass index ≥30.0 (%)
429 (21.9)
4085 (14.6)
1.57 (1.40 –1.76)* 0.56 (0.33 –0.96)*
Psychiatric disorders (%) Hepatitis C/HIV (%) Body mass index ,18.0 (%)
14 (0.7)
340 (1.2)
Assisted conception (%)
85 (4.2)
653 (2.3)
1.83 (1.45 –2.31)*
Previous termination (%)
84 (4.1)
1828 (6.5)
0.62 (0.50 –0.77)*
Previous perinatal death (%)
71 (3.5)
439 (1.6)
2.28 (1.77 –2.94)*
Fetal complication (%)
160 (7.9)
2043 (7.3)
1.09 (0.92 –1.29)
Antenatal complication (%)
136 (6.7)
1557 (5.6)
1.22 (1.02 –1.46)*
Pre-eclampsia/PIH (%)b
78 (3.8)
1307 (4.7)
0.82 (0.65 –1.03)
Abruption/APH (%)c
20 (1.0)
183 (0.7)
1.51 (0.95 –2.41)
127 (0.5)
2.63 (1.70 –4.08)*
Placenta praevia (%) Spontaneous vaginal delivery
24 (1.2) 1204 (59.3)
16 275 (58.1)
Operative vaginal delivery
202 (10.0)
4950 (17.7)
0.52 (0.44 –0.60)*
Caesarean section scheduled
342 (16.8)
3002 (10.7)
1.69 (1.49 –1.91)*
Caesarean section emergency
282 (13.9)
3796 (13.5)
1.03 (0.90 –1.17)
a
1.05 (0.96 –1.15)
Diabetes includes pre-existing diabetes and gestational diabetes. PIH pregnancy induced hypertension, not all women delivered for PIH had a completed 24 h urine collection and some may have had pre-eclampsia. c All cases of placental abruption and antepartum haemorrhage requiring delivery. *P , 0.05. b
1243
Perinatal outcomes after recurrent miscarriage
Table III Perinatal outcomes according to history of recurrent miscarriage. Recurrent miscarriage n 5 2030 (%)
Not recurrent miscarriage n 5 28 023 (%)
Adjusted ORa (95% CI)
Difference in means (95% CI) Odds ratio (95% CI)
............................................................................................................................................................................................. Gestational age (weeks), mean (SD)
39.1 (2.3)
39.6 (2.0)
20.5 (20.6 to 20.4)
–
Birthweight (grams), mean (SD)
3417 (652)
3442 (583)
225 (252 to 2)
–
165 (8.1)
1551 (5.5)
1.51 (1.28 to 1.79)*
1.54 (1.29 to 1.84)*
Preterm birth ,37 weeks (%) Very preterm birth ,32 weeks (%) Birthweight ,10th centile (%) Male infant (%)
44 (2.2)
331 (1.2)
1.85 (1.35 to 2.55)*
1.80 (1.28 to 2.53)*
263 (13.0)
3481 (12.4)
1.05 (0.92 to 1.20)
1.07 (0.93 to 1.23)
1034 (50.9)
14 449 (51.6)
0.98 (0.89 to 1.07)
0.98 (0.89 to 1.07)
1.68 (1.12 to 2.53)*
1.54 (0.98 to 2.42)
Apgar score ,7 at 5 min (%)
26 (1.3)
215 (0.8)
Admitted to neonatal unit (%)
307 (15.1)
3940 (14.1)
1.09 (0.96 to 1.24)
1.13 (0.99 to 1.30)
14 (0.7)
204 (0.7)
0.95 (0.55 to 1.63)
0.84 (0.47 to 1.48)
4 (0.2)
49 (0.2)
1.13 (0.41 to 3.13)
0.72 (0.26 to 2.03)
25 (1.2)
154 (0.5)
2.26 (1.48 to 3.45)*
2.66 (1.70 to 4.14)*
Congenital abnormality (%) Aneuploidy (Trisomy/XO) (%) Perinatal death (%)
a Adjusted for maternal age, marital status, SE group, parity, medical disorders, psychiatric disorders, BMI, assisted conception, previous perinatal death. *P , 0.05.
Table IV Perinatal outcomes according to history of primary or secondary recurrent miscarriage. Primary recurrent miscarriage n 5 382 (%)
Secondary recurrent miscarriage n 5 1648(%)
Difference in means (95% CI) Odds ratio (95% CI)
Difference in means (95% CI) Adjusted ORa (95% CI)
............................................................................................................................................................................................. Gestational age (weeks), mean (SD)
39.2 (2.6)
39.1 (2.3)
0.1 (20.2 to 0.4)
–
Birthweight (grams), mean (SD)
3324 (635)
3438 (654)
2114 (2186 to 242)
–
Preterm birth ,37 weeks (%)
33 (8.6)
132 (8.0)
1.09 (0.73 to 1.62)
1.21 (0.79 to 1.87)
Very preterm birth ,32 weeks (%)
12 (3.1)
32 (1.9)
1.64 (0.84 to 3.21)
1.75 (0.83 to 3.69) 0.82 (0.57 to 1.19)
Birthweight ,10th centile (%)
42 (11.0)
221 (13.4)
0.80 (0.56 to 1.13)
197 (51.6)
837 (50.8)
1.03 (0.83 to 1.29)
1.00 (0.81 to 1.27)
Apgar score ,7 at 5 min (%)
7 (1.8)
19 (1.2)
1.61 (0.67 to 3.86)
1.24 (0.45 to 3.39)
Admitted to neonatal unit (%)
79 (20.7)
228 (13.8)
1.62 (1.22 to 2.16)*
1.76 (1.29 to 2.39)*
Congenital abnormality (%)
3 (0.8)
11 (0.7)
1.18 (0.33 to 4.24)
0.97 (0.24 to 3.98)
Aneuploidy (Trisomy/XO) (%)
0 (0.0)
4 (0.2)
Perinatal death (%)
5 (1.3)
20 (1.2)
Male infant (%)
– 1.08 (0.40 to 2.90)
– 1.15 (0.41 to 3.28)
a Adjusted for maternal age, marital status, SE group, medical disorders, psychiatric disorders, BMI, assisted conception, previous perinatal death. *P , 0.05.
dating of each pregnancy, and routine ascertainment of the perinatal outcomes of interest. The large sample size and detailed dataset allowed us to perform robust analyses of less common outcomes including very preterm birth and perinatal death. This is a retrospective cohort study and while regression analyses adjusted for potential confounding factors, residual confounding may persist. The strict definition of recurrent miscarriage is three consecutive miscarriages and while each woman in the study group had three or more miscarriages, these were not necessarily consecutive or with the same partner. However, adverse perinatal outcomes were very similar for both primary and secondary RM. The affected women had not been categorized according to aetiology of recurrent miscarriage and it may be that adverse outcomes
differ according to aetiological subgroup. However, many women with a history of three or more miscarriages book for antenatal care without prior assessment at a recurrent miscarriage clinic, and of those who have been assessed, approximately half will be diagnosed with unexplained RM (Clifford et al., 1994).
Comparison with existing literature The prevalence of RM as defined within our cohort was 6.8% with almost one in five women experiencing primary RM. This equates with an overall population prevalence of 1.3% for primary RM, in keeping with other studies (Stirrat, 1990; Carrington et al., 2005). Some studies have
1244 defined RM as two or more consecutive spontaneous miscarriages (Bhattacharya et al., 2010; Bashiri et al., 2012) and one study reported an association with placental abruption, hypertensive disorders and Caesarean section (Sheiner et al., 2005). Women with two miscarriages were included in the comparison group for our analyses, which if anything would result in an underestimation of the true association between recurrent RM and adverse perinatal outcome. There was clear evidence of an association between RM and obesity in keeping with the findings of others (Metwally et al., 2010; Lo et al., 2012). While we did not look specifically at the association between increased BMI and adverse perinatal outcome, this association has been well documented (Rosenberg et al., 2003; Cedergren, 2004). Many studies have investigated the relationship between hypothyroidism and recurrent miscarriage. Similar to the study by Bernardi et al. (2013), we did not find any strong evidence to suggest that there is a difference in the subsequent pregnancy outcome of women with a history of RM and hypothyroidism. The association between RM and assisted conception is also well recognized and, as with scheduled Caesarean section, it is difficult to differentiate the impact of cause and effect. Unlike other studies, we did not find a significant association between RM and pre-eclampsia or placental abruption (Sheiner et al., 2005; Trogstad et al., 2009). The association between RM and placenta praevia is striking and may reflect repeated surgical evacuation of retained products of conception among this group. The literature to date has focused mainly on whether or not a pregnancy is achieved following RM and the effectiveness of therapeutic options, taking account of specific aetiological subgroups and idiopathic RM (Tang and Quenby, 2010; Duckitt and Qureshi, 2011). The data on perinatal outcomes are more limited. Some studies have reported similar findings to ours with an association between RM and preterm delivery, perinatal death and delivery by Caesarean section, however the numbers included were small with limited attention to confounding factors (Jivraj et al., 2001). Dempsey et al. (2014) reported no significant increase in the risk of growth restriction, delivery by Caesarean section or perinatal death in a prospective cohort of women with unexplained RM, however only 42 women were studied. Our study showed similar perinatal outcomes for women who experienced primary RM and secondary RM, apart from an increase in the number of infants admitted to the neonatal unit following primary RM. This contrasts with a study by Shapira et al. (2012) who reported a significantly higher incidence of preterm birth in the primary RM group, based on a study size of 420 women. In 2009, Van Oppenraaij et al. published a review of the literature on adverse obstetric outcomes after early pregnancy complications, including recurrent miscarriage. They focused on the obstetric and perinatal outcomes following RM and found only one study that distinguished between the underlying cause for the RM and idiopathic RM. They concluded that larger studies addressing the risk of adverse perinatal outcome in women with idiopathic RM were needed. While our study did not distinguish between idiopathic RM and those with an underlying cause, our analyses adjusted for known preexisting medical disorders.
Implications for practice This study highlights the need for specialist obstetric care for women who have had three or more previous miscarriages, regardless of whether or not they are consecutive. Factors associated with RM included obesity,
Field and Murphy
assisted conception and pre-existing medical disorders. Pre-pregnancy planning should target weight loss and optimization of health and wellbeing prior to attempting pregnancy. The associations between RM and prematurity, perinatal death and scheduled Caesarean section are likely to be related. A management schedule addressing these risks should be put in place with maternal and fetal monitoring that addresses common underlying pathologies, including fetal growth restriction, placental dysfunction, pre-eclampsia and spontaneous preterm labour.
Conclusions This study provides important information for counselling women with a history of three or more miscarriages. These women should be offered specialist obstetric care from the start of pregnancy with an emphasis on strategies to manage the increased risk of preterm birth and perinatal death.
Acknowledgements We would like to thank the midwives and other staff members who collect the data with great care and the IT and B Cleary who helped with data extraction and coding.
Authors’ roles K.F. interpreted the data and drafted the manuscript. D.J.M. had the idea for the study, performed the analyses, interpreted the data and assisted with drafting of the manuscript. D.J.M. is the guarantor.
Funding No external funding was either sought or obtained for this study.
Conflict of interest None declared.
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