Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case–control study

H. Lashen1,3, K. Fear2 and D.W. Sturdee2

1 New Jessop Wing, Obstetrics and Gynaecology, University of Sheffield, Sheffield S10 2SF and 2 Department of Obstetrics and Gynaeology, Solihull Hospital, Birmingham Heartlands and Solihull Hospitals NHS Trust, Solihull, West Midlands B91 2JL, UK

3 To whom correspondence should be addressed. e-mail: h.lashen{at}sheffield.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Obesity has become a major health problem worldwide and is also associated with adverse pregnancy outcome. The aim of this study was to assess the impact of obesity on the risk of miscarriage in the general public. METHODS: This was a nested case–control study. The study population was identified from a maternity database. Obese [body mass index (BMI) >30 kg/m2] women were compared with an age-matched control group with normal BMI (19–24.9 kg/m2). Only primiparous women were included in the study to avoid including the subject more than once, and to be able to correctly identify recurrent miscarriages. The prevalence of a previous history of early (6–12 weeks gestation), late (12–24 weeks gestation) and recurrent early miscarriages (REM) (more than three successive miscarriages <12 weeks) was compared between the two groups. RESULTS: A total of 1644 obese and 3288 age-matched normal weight controls with a mean age of 26.6 years [95% confidence interval (CI) 26.5–26.7] were included in the study. The risks of early miscarriage and REM were significantly higher among the obese patients (odds ratios 1.2 and 3.5, 95% CI 1.01–1.46 and 1.03–12.01, respectively; P = 0.04, for both]. CONCLUSIONS: Obesity is associated with increased risk of first trimester and recurrent miscarriage.

Key words: obesity/miscarriage/recurrent miscarriage


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Obesity has become a major health problem across the world. In the UK, obesity affects one-fifth of the female population (Anonymous, 2001Go). Maternal obesity has been reported as a risk factor for adulthood obesity in offspring (Parsons et al., 2001Go). Obesity may also lead to a poor pregnancy outcome, such as sudden and unexplained intrauterine death (Froen et al., 2001Go), and in women with polycystic ovary syndrome (PCOS) receiving infertility treatment is associated with an increased risk of miscarriage (Hamilton-Fairley et al., 1992Go; Wang et al., 2000Go). However, in the general population there is less evidence for a link between obesity and spontaneous miscarriage (Risch et al., 1990Go). The aim of this study was to determine whether there is any association between obesity and the risk of spontaneous miscarriage in a general population.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The database of Solihull Maternity Unit from 1985 to 1999 was reviewed. This is a comprehensive, prospectively collected database that records maternal gynaecological and obstetric history, as well as current pregnancy details and outcome. All data are entered at the time of birth; therefore, all the participants in this study gave birth to their first child during that period. The outcome of previous pregnancies of all women who delivered during the study period was retrieved. Only miscarriages occurring after 6 weeks gestation were recorded to avoid confusion with early pregnancy loss. The body mass index (BMI) of all mothers at booking (10–14 weeks gestation) was calculated using the Quintelet formula (weight in kg/height in meters squared).

Obese women (BMI >30 kg/m2) and an age-matched control group with normal BMI (19–24.9 kg/m2) were included in the study, based on the WHO criteria. For every obese woman, two age-matched normal weight (BMI 19–24.9) controls were selected at random from the next database entry.

The two groups were compared with regard to their previous history of early (6–12 weeks gestation), late (12–24 weeks gestation) and recurrent early (more than three) miscarriages using binary logistic regression analysis.

The prevalence of pre-pregnancy diabetes mellitus and gestational diabetes based on impaired oral glucose tolerance test (post prandial glucose of >7.5 mmol/l) were also compared between the two groups. Statistical analysis was carried out using Minitab for Windows, release 13.32 (Minitab Inc., PA, USA). The data are presented as mean or odds ratios (ORs) with the relevant 95% confidence intervals (CIs). A P-value <0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 1644 obese women and 3288 normal weight controls (NWC) were included in the study. The percentages (95% CI) of early, late and recurrent early miscarriage (REM) in the obese group were 12.5% (10.9–14), 2% (1.5–2.5) and 0.4% (0.1–0.7), respectively. The same measures in the NWC group were 10.5% (9.5–11.5), 2% (1.5–2.5) and 0.1% (0.02–0.2), respectively. The relative risks were 1.25, 1 and 4 for early, late and recurrent miscarriages, respectively. The obese women had a significantly higher incidence of early and recurrent early miscarriages compared with the NWC (P = 0.04). The ORs (95% CI) are 1.2 (1.01–1.46) and 3.51 (1.03–12.01) for early miscarriage and REM, respectively.

The prevalence of diabetes mellitus in the two groups was very low, as only four patients in the obese group (0.2%) and none in the NWC group had pre-pregnancy diabetes. The prevalence of gestational diabetes was significantly higher among the obese patients (4.5%; 95% CI 3.5–5.5) compared with the NWC group (0.4%; 95% CI 0.2–0.6). This difference was statistically significant (OR 13.05; 95% CI 7.07–24.07). P <0.001.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Spontaneous miscarriage affects 12–15% of all pregnancies (Zinman et al., 1996Go). Eighty percent of miscarriages occur before 12 weeks of gestation, and the majority are due to chromosomal abnormalities (Harlap et al., 1980Go). Our figures from this study population are consistent with previously published data.

The risk of miscarriage after the detection of a fetal heart on ultrasound scan is reduced to 5%, except in patients who have had recurrent miscarriages (van Leeuwen et al., 1993Go).

Many factors have been described to increase the risk of spontaneous miscarriage; however, obesity was not found to be a risk factor by Risch et al. (1990)Go. Recent evidence indicated that obese women undergoing infertility treatment were at increased risk of spontaneous miscarriage (Hamilton-Fairley et al., 1992Go; Wang et al., 2000Go). However, this point has also been controversial (Lashen et al., 1999Go; Roth et al., 2003Go).

In this study, we compared the incidence of early, late and recurrent miscarriage between a group of obese women and a randomly selected group of age-matched NWC. This is the first study of its kind, nested case–control, to assess such relationship in the general population according to the timing of miscarriage, i.e. early or late. Furthermore, this is also the first study to examine the prevalence of recurrent miscarriage among obese women in comparison with NWC. The exact reason for the obesity-related increased risk of miscarriage is not known. The possibility of oocyte abnormality was refuted by a recent study of obese women receiving oocyte donation who experienced a higher rate of spontaneous miscarriage compared with normal weight peers (Bellver et al., 2003Go). The prevalence of overweight and obesity among PCOS patients is ~50% (Pasquali and Casimirri, 1993Go). Therefore, it is unlikely that the increased risk of miscarriage among obese patients in this study population can solely be attributed to PCOS, owing to the low prevalence of PCOS in this general population with mostly spontaneous miscarriage. Furthermore, evidence has been reported that obesity is an independent risk factor for miscarriage (Fedorcsak et al., 2000Go). Furthermore, Wang et al. (2001)Go suggested that spontaneous abortion reported in women with PCOS may be due to their high prevalence of obesity.

A four-fold increase in the risk of spontaneous miscarriage was reported in diabetic pregnant women with poor glycaemic control in early pregnancy (Temple et al., 2002Go). However, in our study population the prevalence of pre-pregnancy diabetes was very low, precluding further assessment of this point. Notably, a higher incidence of gestational diabetes was observed in the obese group, which reflects an unphysiological insulin resistance that may play a role in the reported increased miscarriage risk. One could argue that type II and gestational diabetes are one condition differing in the time of detection, and that the worse the insulin resistance at the time of conception and in early pregnancy the higher the risk of miscarriage. This hypothesis can not be addressed in the context of this study, and perhaps a prospective cohort study is better suited to address this issue.

Endometrial receptivity is yet another plausible explanation for early miscarriage; however, evidence is lacking to rule out the oocyte as a potential cause. An unfavourable intrauterine milieu associated with obesity is an alternative explanation for the increased prevalence of miscarriage. However, the fact that all these patients had a successful pregnancy suggests a non-recurring cause for the miscarriage, pointing again to the oocyte quality issue. The retrospective nature of this study and the lack of some information regarding the patients who miscarried but who were not included in the database preclude identification of the cause for the increased risk of miscarriage in the obese population. Furthermore, some may argue that obesity can confer a protective effect in some obese patients, hence their successful pregnancy on this occasion. The weight of evidence so far does not support this hypothesis, and a specially designed cohort study is better suited to address it. This nonetheless, does not reduce the value of this study in identifying a link between obesity and early and recurrent miscarriages. A more precise cause is a prime subject for future research, which is justifiable in view of our and other researchers’ findings.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Anonymous (2001) Tackling Obesity in England. Report by the Comptroller and Auditor General. HC 220 Session 2000–2001, 15 February 2001. Ordered by the House of Commons to be printed on 8 February. The Stationary Office, London, UK.

Bellver J, Rossal LP, Bosch E, Zuniga A, Corona JT, Melendez F, Gomez E, Simon C, Remohi J and Pellicer A (2003) Obesity and the risk of spontaneous abortion after oocytes donation. Fertil Steril 79,1136–1140.[CrossRef][Medline]

Fedorcsak P, Storeng R, Dale PO, Tanbo T and Abyholm T (2000) Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gynaecol Scand 79,43–48.[CrossRef][Medline]

Froen JF, Amestad M, Frey K, Vege A, Saugstad OD and Stray-Pedersen B (2001) Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986–1995. Am J Obstet Gynecol 184,694–702.[CrossRef][Medline]

Hamilton-Fairley D, Kiddu D, Watson H, Peterson C and Franks S (1992) Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin. Br J Obstet Gynaecol 99,128–131.[Medline]

Harlap S and Shiono PH (1980) Alcohol, smoking, and incidence of spontaneous abortions in the first and second trimester. Lancet ii,173–176.

Lashen H, Ledger W, Lopes-Bernal A and Barlow D (1999) Extreme of body mass index do not adversely affect the outcome of superovulation and in-vitro fertilisation. Hum Reprod 14,712–715.[Abstract/Free Full Text]

Parsons TJ, Power C and Manor O (2001) Fetal and early life growth and body mass index from birth to early adulthood in 1958 British cohort: longitudinal study. BMJ 323,1331–1335.[Abstract/Free Full Text]

Pasquali R and Casimirri F (1993) The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women. Clin Endocrinol 39,1–16.[Medline]

Risch HA, Weiss NS, Clarke EA and Miller AB (1990) Risk factors for spontaneous abortion and its recurrence. Am J Epidemiol 131,570–573.[Medline]

Roth D, Grazi RV and Lobel SM (2003) Extremes of body mass index do not affect first trimester pregnancy outcomes in patients with infertility. Am J Obstet Gynaecol 188,1169–1170.[CrossRef][Medline]

Temple R, Aldridge V, Greenwood R, Heyburn P, Sampson M and Stanley K (2002) Association between outcome of pregnancy and glycaemic control in early pregnancy in type I diabetes: population based study. BMJ 325,1275–1276.[Free Full Text]

vanLeeuwen I, Branch DW and Scott JR (1993) First trimester ultrasonography findings in women with a history of recurrent pregnancy loss. Am J Obstet Gynecol 168,111–114.[Medline]

Wang JX, Davies M and Norman RJ (2000) Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ 321,1320–1321.[Free Full Text]

Wang JX, Davies MJ and Norman RJ (2001) Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 16,2606–2609.[Abstract/Free Full Text]

Zinman MJ, Clegg DE, Brown CC, O’Connor J and Selvan SG (1996) Estimates of human fertility and pregnancy loss. Fertil Steril 65,503–509.[Medline]

Submitted on October 8, 2003; accepted on March 29, 2004.