Beta Fulltext view is in preview — article structure may vary. Browse all articles
Contents
Open Access Journal of Endocrinology Research Article 15 min read

Endocrinological and Environmental Causes of Recurrent Miscarriage: A Review

<p>Barrenetxea G*, Ortuzar M and Barrenetxea J</p>
* Corresponding author
ISSN: 2578-4641  10.23880/oaje-16000111  Received: June 05, 2017  Published: July 04, 2017
 — views
 52 references
 2 tables
PDF
Keywords
<p>Recurrent miscarriage Endocrinological etiology Environmental etiology Obesity Smoking Alcohol consumption</p>
Abstract

<p>Early pregnancy loss is perhaps the most common obstetric complication, occurring in over two-thirds of human conceptions. Approximately 15 – 20% of all clinically recognized pregnancies will end in a miscarriage. Approximately, 1% of all women trying to conceive have recurrent miscarriage, defined as three previous miscarriages. Despite thorough examinations to exclude several well-known etiologic factors, the cause for recurrent spontaneous abortion can often not be found in almost 50% of cases In addition to genetic or auto-immune diseases, endocrine dysfunction and metabolic disorders have been implicated. The purpose of this review is to update potential endocrinological causes of RM including thyroid disease, diabetes mellitus, hyperprolactinemia and polycystic ovarian syndrome. Also, obesity, hyperandrogenism, luteal phase defects and environmental, occupational or personal habits, such as cigarette smoking or alcohol consumption, are assessed as potential etiologies of recurrent miscarriage.</p>

Introduction

Human reproduction is characterized by its inefficiency. Early pregnancy loss is perhaps the most common obstetric complication, occurring in over two- thirds of human conceptions [1]. Approximately 15 – 20% of all clinically recognized pregnancies will end in a miscarriage [2, 3, 4, 5]. However, prospective cohort studies using sensitive and specific daily urinary hCG assays in women trying to conceive have demonstrated that only around one-third of conceptions progress to a live birth [6]. Most of the losses occur before the clinical recognition of pregnancy as implantation failures. An estimated 30% of human conceptions are lost prior to implantation and a further 30% following implantation but before the missed menstrual period, that is in the third or fourth week of gestation. These are often termed preclinical losses [2, 7].

For more than 30 years, controversy has existed on the number of miscarriages required to define recurrent miscarriage (RM) and when diagnostic testing is warranted [8]. The definition ranges from two clinical miscarriages, not necessarily consecutive, according to the American Society for Reproductive Medicine (ASRM) and a joint International Committee for Monitoring Assisted Reproductive Technology and World Health Organization glossary, affecting more than 3% of couples desiring a baby to three consecutive pregnancy losses (not necessarily intra-uterine) as defined by both the European Society for Human Reproduction and Embryology and the Royal College of Obstetricians and Gynecologists and affecting 1% of couples trying to conceive [9, 10, 11, 12, 13, 14, 15, 16]. After defining RM as the diagnosis of two or more failed clinical pregnancies, the American Society for Reproductive Medicine (ASRM) recommended that ‘‘a threshold of three or more losses should be only used for epidemiological studies while clinical evaluation may proceed following two first-trimester pregnancy losses’’ [9]. To address this controversy there were evaluated more than 1,000 women with RM, and, no differences were found in the frequency of abnormal diagnostic factors between women with two and those with three or more miscarriages, argued that full evaluations should be offered to women who have experienced at least two consecutive pregnancy losses [8, 17]. It is estimated that fewer than 5% of women will experience two consecutive miscarriages, and only 1% experience three or more [18, 19]. Compared to sporadic miscarriage the prevalence of RM is considerably lower irrespective of whether biochemical losses are included or not. Approximately 1% of all women trying to conceive have recurrent miscarriage, defined as three previous miscarriages; when recurrent miscarriage is defined as two previous miscarriages, the proportion rises to 5% [20, 21, 22]. For the purposes of determining whether evaluation for RM is appropriate, pregnancy is defined as a clinical pregnancy documented by ultrasonography or histopathological examination [2]. Ideally, a threshold of three or more losses should be used for epidemiological studies while clinical evaluation may proceed following a second miscarriage [19].

Etiology

The potential etiologies of RM can be divided into embryologically driven causes (mainly due to an abnormal embryonic karyotype) and maternally driven causes which affect the endometrium and/or placental development [24, 25]. Thus, studies that focus on RM have examined factors related to age, genetics, antiphospholipid syndrome, uterine anomalies, thrombophilias, hormonal or metabolic disorders, infection, autoimmunity, sperm quality, and life-style issues (Table 1). Also, several recommendations have been published regarding the evaluation and management of RM [16]. Despite thorough examinations to exclude several well- known etiologic factors, the cause for recurrent spontaneous abortion can often not be found in almost 50% of cases [23, 26]. These are termed unexplained recurrent miscarriages. In recent years, progress in the fields of cytogenetics and immunogenetics and a greater understanding of implantation and maternal-embryo interactions has offered new insights into the possible causes of this condition, and opened new avenues for research into its prevention and treatment [2]. But, in addition to genetic or auto-immune diseases, endocrine dysfunction and metabolic disorders have been implicated [27, 28, 29]. The purpose of this review is to update potential endocrinological causes of RM.

Hormonal and Metabolic Etiologies of Recurrent Miscarriage

It is generally agreed that maternal endocrine disorders (e.g., thyroid dysfunction, diabetes) should be evaluated and treated in cases of RM [30, 31]. The prevalence of hypothyroidism with or without underlying thyroid autoimmunity is significant among women in fertile age. There is evidence that thyroid dysfunction and thyroid autoimmunity is associated with infertility and pregnancy loss both in the situation where the woman is euthyroid with thyroid antibodies and in a thyroid antibody negative woman with an elevated level of thyroid stimulating hormone (TSH) [31]. As long as thyroid-stimulating hormone (TSH) levels are in the normal range, there is insufficient evidence to recommend routine thyroxine (T4) testing or screening for anti-thyroid antibodies [32]. According to a recent meta-analysis of 38 studies, the presence of antibodies against thyroperoxidase (TPO-Ab) increased the risk of sporadic miscarriage with an odds ratio of 3.73 (95% CI 1.8 to 7.6) as well as RM (OR 2.3, 95% CI 1.5 to 3.5) [33]. However, this is problematic given the lack of consensus regarding the definition of a normal upper limit of TSH. Whereas TSH values of 4.0–5.0 mIU/L were once considered normal, a consensus is emerging that TSH values above 2.5 mIU/L are outside the normal range. In a large prospective study including pregnant thyroid antibody negative women, a TSH level within the normal range but higher than 2.5 mIU/L in the first trimester, nearly doubled the risk of a miscarriage [34]. However, the true significance of thyroid dysfunction and the value of its correction in improving outcomes in RM remains unclear [35]. The prevalence of diabetes mellitus in women who suffer recurrent miscarriage is similar to that reported in the general population [36]. Current evidence shows that well-controlled diabetes is not a risk factor for RM. However, uncontrolled diabetes is associated with increased pregnancy loss thus, attention should first be given to optimal metabolic control of diabetic women during the preconceptional period [37, 38]. Prolactin is commonly measured because elevated prolactin levels are associated with ovulatory dysfunction. Hyperprolactinemia may be associated with recurrent pregnancy loss through alterations in the hypothalamic- pituitary-ovarian axis, resulting in impaired folliculogenesis and oocyte maturation, and/or a short luteal phase. Normalization of prolactin levels with a dopamine agonist improved subsequent pregnancy outcomes in patients with recurrent pregnancy loss [39]. Patients (n 1⁄4 64) with 2 or more pregnancy losses and hyperprolactinemia were treated with bromocriptine in their next pregnancy. Treatment resulted in an 85.7% live-born rate, whereas the untreated cohort had a 52.4% live-born outcome [39]. The role of other hormonal abnormalities remains controversial. Polycystic ovarian syndrome (PCOS) is a common endocrine disorder of reproductive-age women. PCOS may be associated with ovulatory disorder and miscarriage when fertility is desired. It has been estimated that 40% of pregnancies in women with PCOS will result in spontaneous loss [38]. However, using strict criteria the prevalence of PCOS among women with RM is estimated to be 8.3% to 10% [40]. Polycystic ovary syndrome (PCOS) has been linked to an increased risk of miscarriage but the exact mechanism remains unclear. Polycystic ovarian morphology, elevated serum luteinizing hormone levels or elevated serum testosterone levels, although markers of PCOS, do not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously [22]. The mechanisms behind an increased miscarriage risk in women with PCOS remains partly unclear. The current view is that the main cause may be the associated obesity, as well as insulin resistance, hyperinsulinemia and hyperandrogenemia.

Retrospective evidence suggests that obesity increases the risk of miscarriage [41]. Obese women with RM have a higher frequency of euploid miscarriage compared with non-obese women. Obesity is associated with many endocrine disorders, such as diabetes, hypothyroidism, and PCOS, which, theoretically, could result in an increased risk of euploid miscarriage due to suboptimal implantation related to endocrine changes. It is thought that obesity acts on female reproductive function through hyperinsulinemia and, consequently, through its effect on androgen production. Some authors have argued that insulin resistance is a key factor in explaining the association between obesity, PCOS and recurrent miscarriages [42]. The prevalence of insulin resistance is increased in women with recurrent miscarriage compared with matched fertile controls. An elevated free androgen index appears to be a prognostic factor for a subsequent miscarriage in women with recurrent miscarriage [40]. Metformin treatment of PCOS patients decreases insulin resistance, thus improving ovulation cycles and, therefore, conception rates in infertile women but it is uncertain whether it decreases the rate of miscarriage in PCOS patients as no proper RCT has been conducted [37]. Boots and Stephenson completed a systematic review evaluating whether obesity increases the rate of miscarriage in spontaneously conceived pregnancies [43]. Overall, 3,800 obese, 3,792 overweight, and 17,146 normal weight women were included in the pooled analysis. The percentages of women with RM were 16.6%, 11.8%, and 10.7%, respectively. The odds of having RM were increased for obese women (odds ratio [OR] 1.31, 95% CI 1.18–1.46) and overweight women (OR 1.11, 95% CI 1.00– 1.24), when compared with women with normal BMI. Different retrospective studies have suggested a relationship of obesity and miscarriage, either sporadic or recurrent [44]. Furthermore, in 2010, Landres, et al. [45] reported a significant increase in euploid (46,XX or 46,XY) miscarriages in overweight or obese women (BMI R25 kg/m2) compared with women of normal weight (BMI <25 kg/m2), in a retrospective case-control study of 204 miscarriages from an infertility practice. More recently, Boots et al showed in a powerful study that obese women with recurrent miscarriage were also more likely to have euploid miscarriages and, therefore, are at an increased risk of subsequent miscarriages [41]. Conceptually, delayed or late implantation may increase pregnancy losses [46]. A shortened luteal phase has been associated with pregnancy loss but the assessment and interpretation of a putative luteal phase defect is problematic [47]. The use of histologic and biochemical end-points as diagnostic criteria for endometrial dating are unreliable and not reproducible utilizing the traditional histological criteria or other biochemical approaches. Therefore, routine endometrial biopsy for dating is not recommended, although continued research on the emerging molecular markers of endometrial development should be encouraged [3]. Administration of progesterone to women with sporadic miscarriages is ineffective [48]. However, in patients with three or more consecutive miscarriages immediately preceding their current pregnancy, empiric progestogen administration may be of some potential benefit [49].

Environmental, Occupational or Personal Habits

The evidence on the effect of environmental risk factors is based mainly on data studying women with sporadic rather than RM. The results are conflicting and biased by difficulties in controlling for confounding factors and the inaccuracy of data on exposure and the measurement of toxin dose.

Maternal cigarette smoking and caffeine consumption have been associated with an increased risk of spontaneous miscarriage in a dose-dependent manner. Smoking-related complications in late pregnancy are substantial and well documented. However, current evidence is insufficient to confirm the association with miscarriage [2]. Nevertheless, cigarette smoking has been suggested to have an adverse effect on trophoblastic function and a link to an increased risk of sporadic pregnancy loss has been suggested [50]. A recent review reports an increased risk of pregnancy loss among smokers whereas a large prospective study including 24.608 pregnancies could not demonstrate an association between smoking and miscarriage [51, 52]. Other life-style habits such as cocaine use, alcohol consumption (3 to 5 drinks per week), and increased caffeine consumption (>3 cups of coffee), have been associated with risk of miscarriage. Heavy alcohol consumption is toxic to the embryo and the fetus. Even moderate consumption of five or more units per week may increase the risk of sporadic miscarriage [2, 16, 19].

ControversialrNotd
EtiologyScreeningManagement
evidenceecommende
Genetic abnormalitiesEmbryonic
chromosomal
abnormalities		Genetic analysis of
products of
conception		Preimplantational
genetic screening
Parental balanced
reciprocal
translocations		Parental karyotypePreimplantational
genetic screening
Sperm DNA
fragmentation
Thrombotic disordersHereditary
thrombophilia		Thrombotic testsHeparin, LDA
Antiphospholipid
syndrome		LAC, ACA IgG & IgM
antibody
AlloimmunityUterine NK cells,
cytokine profiles		Circulating NK
cells
HLA typing

Table 1: Possible causes of Recurrent Miscarriage (RM). LDA: low.dose aspirin. LAC: lupus antiocoagulant.ACA: anticardiolipin ant

Uterine anatomic
abnormalities		Congenital uterine
malformations		MRI
3D-ultrasound		Hysteroscopy:
septal resection
Adquired anatomic
disorders		MRI
3D-ultrasound		HysteroscopyTreatment of
myomas		Cervical
incompetence
Hormonal/metabolic
etiology		Hypotidoidism,
hyperprolactinemia,
diabetes mellitus
polycystic ovarian
syndrome		TSH, PRL, Hb A1CLevothyroxineInsulin resistanceLuteal phase
progesterone
Environmental,
occupational, personal
habits.		AnamnesisAlcohol cessationWeight loss

Table 2: Possible causes of Recurrent Miscarriage (RM). LDA: low.dose aspirin. LAC: lupus antiocoagulant.ACA: anticardiolipin ant

Possible Etiologies of Recurrent Miscarriages

1. Genetic abnormalities

  • Embryonic chromosomal abnormalities
  • Parental balanced reciprocal translocations 2. Thrombotic disorders
  • Thrombophilia
  • Adquired thrombophilic conditions: antiphospholipid syndrome
  • Alloimmunity 3. Uterine anatomic abnormalities
  • Congenital uterine malformations
  • Adquired anatomic disorders 4. Hormonal/metabolic etiology
  • Hypotiroidism
  • Diabetes mellitus
  • Hyperprolactinemia
  • PCOS
  • Lutelphasedeffect
  • Obesity 5. Environnmental, occupational, personal habits.

Summary and clinical implications

The loss of pregnancy at any stage can be a devastating experience and particular sensitivity is required in assessing and counselling couples with RM. Recurrent miscarriage (RM) represents a clinical challenge for physicians not only because there are multiple possible etiologies, but also because the diagnostic testing is costly and time consuming.

In addition to genetic or auto-immune diseases, endocrine dysfunction, metabolic disorders and environmental risk factors may play an important role in the etiology of RM. Thus, diagnosis and management of some endocrinological disorders, including obesity, as well as the modification of some life-style habits may be beneficial in this challenging problem.

References

  1. Silver RM and Warren JE (2006) Preconception Counseling for Women with Thrombophilia. Clin Obstet Gynecol 49(4): 906-919.
  2. Larsen EC, Christiansen OB, Kolte AM and Macklon N (2013) New insights into mechanisms behind miscarriage. BMC Medicine 11: 154-163.
  3. The Practice Committee of the American Society for Reproductive Medicine (2012) Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 98(5): 1103-1111.
  4. Hooker AB, Lemmers M, Thurkow AL, Heymans MW, Opmeer BC, et al. (2014) Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reprod Update 20(2): 262-278.
  5. Wang X, Chen C, Wang L, Chen D, Guang W, et al (2003) Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 79(3): 577–584.
  6. Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG (1996) Estimates of human fertility and pregnancy loss. Fertil Steril 65(3): 503-509.
  7. Macklon NS, Geraedts JP, Fauser BC (2002) Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update 8(4): 333-343.
  8. Jaslow CR, Kutteh WH (2013) Effect of prior birth and miscarriage frequency on the prevalence of acquired and congenital uterine anomalies in women with recurrent miscarriage: a cross- sectional study. Fertil Steril 99: 1916-1922.
  9. ASRM Practice Committee (2013) Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 99(1): 63.
  10. Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, et al. (2009) International Committee for Monitoring Assisted Reproductive Technology and World Health Organization. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology. Hum Reprod 24(11): 2683-2687.
  11. Porter TF, Scott JR (2005) Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol 19(1): 85-101.
  12. Bellver J, Meseguer M, Muriel L, Garcia-Herrero S, Barreto MA, et al. (2010) Y chromosome microdeletions, sperm DNA fragmentation and sperm oxidative stress as causes of recurrent spontaneous abortion of unknown etiology. Hum Reprod 25(7): 1713-1721.
  13. Neusser M, Rogenhofer N, Dürl S, Ochsenkühn R, Trottmann M, et al. (2015) Increased chromosome 16 disomy rates in human spermatozoa and recurrent spontaneous abortions. Fertil Steril 104(5): 1130-1137.
  14. Gupta S, Agarwal A, Banerjee J, Alvarez JG (2007) The Role of Oxidative Stress in Spontaneous Abortion and Recurrent Pregnancy Loss: A Systematic Review. Obstet Gynecol Surv 62(5): 335- 347.
  15. Jauniaux E, Hempstock J, Greenwold N, Graham J. Burton (2003) Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 162: 115- 125.
  16. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage (2011) RCOG Green Top Guideline 17: 1-17.
  17. Jaslow CR, Carney JL, Kutteh WH (2010) Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril 93: 1234-1243.
  18. Stirrat GM (1990) Recurrent miscarriage. Lancet 336(8716): 673-675.
  19. Bulletti C, Flamigni C, Giacomucci E (1996) Reproductive failure due to spontaneous abortion and recurrent miscarriage. Hum Reprod Update 2(2): 118-136.
  20. Carp HJA (2007) Epidemiology of recurrent pregnancy loss. In Recurrent Pregnancy Loss. London, UK: Informa Healthcare.
  21. Kaandorp SP, Goddijn M, van der Post JAM, Hutten BA, Verhoeve HR, et al. (2010) Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage. N Engl J Med 362(17): 1586-1596.
  22. Rai R, Regan L (2006) Recurrent miscarriage. Lancet 368(9535): 601-611.
  23. Kim JO, Lee WS, Lee BE, Jeon YJ, Kim YR, et al. (2014) Interleukin-1beta-511T>C genetic variant contributes to recurrent pregnancy loss risk and peripheral natural killer cell proportion. Fertil Steril 102(1): 206-212.
  24. Laird SM, Tuckerman EM, Cork BA, Linjawi S, Blakemore AIF, et al. (2003) A review of immune cells and molecules in women with recurrent miscarriage. Hum Reprod Update 9 (2): 163-174.
  25. Galgani M, Insabato L, Calì G, Della Gatta AN, Mirra P, et al. (2015) Regulatory T cells, inflammation, and endoplasmic reticulum stress in women with defective endometrial receptivity. Fertil Steril 103(6): 1579-1586.
  26. Raziel A, Herman A, Bukovsky I, Caspi E, Ron-el R (1996) Intravenous immunoglobulin treatment of pregnant patients with unexplained recurrent abortions. Hum Reprod 11(4): 711-715.
  27. Dutta UR, Rajitha P, Pidugu VK and Dalal AB (2011) Cytogenetic abnormalities in 1162 couples with recurrent miscarriages in Southern region of India: report and review. J Assist Reprod Genet 28: 145- 149.
  28. Stephenson MD (1996) Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 66(1): 24-29.
  29. Christiansen OB, Nielsen HS, Kolte A, Pedersen AT (2006) Research methodology and epidemiology of relevance in recurrent pregnancy loss. Semin Reprod Med 24(1): 5-16.
  30. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, et al. (2002) Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 12(1): 63-68.
  31. Twig G, Shina A, Amital H and Shoenfeld Y (2012) Pathogenesis of infertility and recurrent pregnancy loss in thyroid autoimmunity. J Autoimmun 38(2-3): J275-J281.
  32. Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, et al. (2007) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 92(8): S1-47.
  33. Van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, et al. (2011) Significance of (sub) clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update 17(5): 605-619.
  34. Negro R, Schwartz A, Gismondi R, TinelliA, Mangieri T, et al. (2010) Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy.
  35. Subclinical hypothyroidism in the infertile female population: a guideline (2015) Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 104(3): 545-553.
  36. Li TC, Makris M, Tomsu M, Tuckerman EM, Laird SM (2002) Recurrent miscarriage, aetiology, management and prognosis. Hum Reprod 8(5): 463- 481.
  37. Jovanovic L, Knopp H, Kim H, Cefalu WT, Zhu XD, et al. (2005) Elevated pregnancy losses at high and low extremes of maternal glucose in early normal and diabetic pregnancies: evidence for a protective adaptation in diabetes. Diabetes Care 28(5): 1113- 1117.
  38. Pluchino N, Drakopoulos P, Wenger JM, Petignat P, Streuli I, et al. (2014) Hormonal causes of recurrent pregnancy loss (RPL). Hormones 13(3): 314-322.
  39. Hirahara F, Andoh N, Sawai K, Hirabuki T, Uemura T, et al. (1998) Hyper- prolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil Steril 70(2): 246-252
  40. Cocksedge KA, Saravelos SH, Metwally M, Li TC (2009) How common is polycystic ovary syndrome in recurrent miscarriage? Reprod Biomed Online 19(4): 572-576.
  41. Boots CE, Bernardi LA, Stephenson MD (2014) Frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss. Fertil Steril 102(2): 455-459.
  42. Tian L, Shen H, Lu Q, Norman RJ, Wang J (2007) Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. Clin Endocrinol Metab 92(4): 1430-1433.
  43. Boots C, Stephenson MD (2011) Does obesity increase the rate of miscarriage in spontaneous conception: a systematic review. Semin Reprod Med 29(6): 507-513.
  44. Metwally M, Saravelos SH, Ledger WL, Li TC (2010) Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril 94(1): 290- 295.
  45. Landres IV, Milki AA, Lathi RB (2010) Karyotype of miscarriages in relation to maternal weight. Hum Reprod 25(5): 1123-1126.
  46. Wilcox AJ, Baird DD, Weinberg CR (1999) Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 340(23): 1796-1799.
  47. American Society for Reproductive Medicine. Clinical relevance of luteal phase deficiency (2012). Fertil Steril 98: 1112-1117.
  48. Haas DM, Ramsey PS (2008) Progestogen for preventing miscarriage. Cochrane Database Syst Rev 10:CD003511.
  49. Oates-Whitehead RM, Haas DM, Carrier JA (2003) Progestogen for preventing miscarriage. Cochrane Database Syst Rev 4: CD003511.
  50. Lindbohm ML, Sallmen M, Taskinen H (2002) Effects of exposure to environmental tobacco smoke on reproductive health. Scand J Work Environ Health 28(2): 84-86.
  51. Saravelos SH, Regan L (2011) The importance of preconception counseling and early pregnancy monitoring. Semin Reprod Med 29(6): 557-568.
  52. Wisborg K, Kesmodel U, Henriksen TB, Hedegaard M, Secher NJ (2003) A prospective study of maternal smoking and spontaneous abortion. Acta Obstet Gynecol Scand 82(10): 936-941.
More from this journal

Cite this article

BibTeX
APA
RIS
@article{barrenetxea2017,
  title   = {Endocrinological and Environmental Causes of Recurrent Miscarriage: A Review},
  author  = {Barrenetxea G, Ortuzar M and Barrenetxea J},
  journal = {Open Access Journal of Endocrinology},
  year    = {2017},
  volume  = {1},
  number  = {2},
  doi     = {10.23880/oaje-16000111}
}
Barrenetxea G, Ortuzar M and Barrenetxea J (2017). Endocrinological and Environmental Causes of Recurrent Miscarriage: A Review. Open Access Journal of Endocrinology, 1(2). https://doi.org/10.23880/oaje-16000111
TY  - JOUR
TI  - Endocrinological and Environmental Causes of Recurrent Miscarriage: A Review
AU  - Barrenetxea G, Ortuzar M and Barrenetxea J
JO  - Open Access Journal of Endocrinology
PY  - 2017
VL  - 1
IS  - 2
DO  - 10.23880/oaje-16000111
ER  -