INTRODUCTION
Recurrent pregnancy loss (RPL) is not only a physical condition, it involves social, psychological, and spiritual domain of health as defined by WHO.1 RPL is an important reproductive health issue which is physically and emotionally taxing for couples and a challenge to the treating clinicians as well. The incidence of RPL varies widely between reports because of the differences in the definitions and the criteria used as well as the population characteristics.2 Indeed, the risk is between 9% and 12% in women aged less than 35 years but increases to 50% in women aged more than 40 years.3 The incidence varies with the various definitions.
It is important to define recurrent miscarriage with precision as the etiology would make a large difference in evaluation, management, counseling, and prognostication of future pregnancies. Reassurance from the treating clinician is of utmost importance for the psychological wellbeing of the couple (Table 1).
A prior pregnancy history is an important prognostic factor.4 Self-reported losses may not be accurate. Successful outcome will occur in more than two-thirds of couples as in most of the cases it is unexplained.
DEFINITION
Primary RPL refers to multiple losses in a woman with no previous pregnancy losses beyond 20 gestational weeks whereas secondary RPL refers to multiple losses in a woman who has already had a pregnancy beyond 20 gestational weeks. Tertiary RPL refers to multiple pregnancy losses in between normal pregnancies.5 Some clinicians do insist the definition should include RPL with the same partner.
This division is not so important as the etiological factors and prognosis is the same in two groups. Perhaps the incidence of acquired anatomical defects like uterine adhesions and cervical insufficiency may be higher in the secondary RPL group hence evaluation of the uterine cavity should be done in this group.
Most of the cases of RPL are due to more than one factor and it is termed unexplained where the cause is not identified.2
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Early pregnancy loss, also referred to as miscarriage or spontaneous abortion, is defined as the loss of clinical pregnancy before 20 completed weeks of gestational age or 18 weeks after fertilization or if gestational age is unknown, the loss of an embryo/fetus of <400 g. Ectopic, molar, and biochemical pregnancies are thus not included (Table 2).33
Preclinical Pregnancy Loss
This entity is diagnosed by performing serum beta human chorionic gonadotropin (hCG) assays in the late luteal phase prior to the onset of the next menstrual cycle.
Clinical Pregnancy Loss
Clinical pregnancy loss is defined as pregnancy loss following an ultrasound confirmation of a gestational sac.8
Clinical pregnancy loss is divided into:9
- Pre-embryonic when no fetal pole is identified (<5 weeks)
- Embryonic when a fetal pole is identified (5–10 weeks)
- Fetal >10 weeks gestation.
Miscarriage can be further classified as embryonic loss (early miscarriage) when it occurs before 10 gestational weeks and fetal loss (fetal miscarriage) when it occurs after 10 gestational weeks.3 Mid-trimester loss occurs between 12 weeks and 28 weeks of pregnancy. The common causes are anatomical defects and antiphospholipid syndrome. These women will benefit with a hysteroscopic evaluation.10
Late fetal loss occurs between 28 weeks to term.7 The most common cause is preterm labor, preterm premature rupture of membranes, preeclampsia (PE), or congenital malformations. Unexplained stillbirth is even more traumatic than unexplained RPL and merits detailed investigations to ascertain a cause. Thrombophilia screening becomes relevant in women with midtrimester and late pregnancy losses.
Recent reports of large population of women with RPL have helped to characterize the incidence and diversity of this heterogenous disorder and a definite cause of pregnancy loss can be established in over 50% of all couples after thorough evaluation.11
Common established causes include uterine anomalies, antiphospholipid syndrome, hormonal, metabolic disorders, and cytogenetic abnormalities. Other etiologies have been proposed but are still considered controversial such as chronic endometritis, inherited thrombophilia's, luteal phase deficiency, and high sperm DNA fragmentation levels. Over the years, evidence-based treatments such as surgical correction of uterine anomalies or aspirin and heparin for antiphospholipid syndrome12 have improved the outcomes for couples with RPL. However almost half of the cases remain unexplained and are empirically treated using progesterone supplementation, anticoagulation, and/or immune modulatory treatments. Nowadays the invention of newer diagnostic tests like 23-chromosome microarray genetic testing of the products of conception has helped to understand the causes in most of the cases of RPL.104
Regardless of the cause, the long-term prognosis of couples with RPL is good and most eventually achieve a healthy live birth. However multiple pregnancy losses can have a significant psychological toll on affected couples and many efforts are being made to improve treatment and decrease the time needed to achieve a successful pregnancy.
GUIDELINES ON DEFINITION
Recurrent miscarriage defined as the loss of three or more consecutive pregnancies affects 1% of couples trying to conceive. It has been estimated that 1–2% of second trimester pregnancies miscarry before 24 weeks of gestation.
ESHRE Guidelines on RPL-NOV 20178
A diagnosis of RPL could be considered after the loss of two or more pregnancies.
Based on evidence the evaluation may be considered either after 2 or 3 miscarriages and should be decided by the treating clinician and informed choice made by the couple. In couple with risk factors evaluation may be initiated after 2 pregnancy losses.
A pregnancy in the definition is confirmed at least by either serum or urine B-hCG, i.e. including nonvisualized pregnancy losses (biochemical pregnancy losses and/or resolved and treated pregnancies of unknown location). In the nonvisualized pregnancy loss, group pregnancy losses after gestational week 6 are included. If a pregnancy was confirmed by ultrasound and there was complete expulsion of embryo it comes under the definition of miscarriage.
Ectopic, molar pregnancies and implantation failure should not be included in the definition. Pregnancy losses both after spontaneous conception and after ART treatment should be included in the definition.
Recurrent early pregnancy loss (REPL) is the loss of two or more pregnancies before 10 weeks of gestational age.
TERMINOLOGY
The terminology used for pregnancy loss needs to be clear, consistent, and patient-sensitive for the purposes of this guideline. The Guideline Development Group (GDG) recommends the use of “pregnancy loss” as a general term and early embryo loss, first trimester pregnancy loss, and second trimester pregnancy loss when gestation-specific reference is needed.2
We recommend the use of RPL to describe repeated pregnancy demise and to reserve RPL to describe cases where all pregnancies have been confirmed as intrauterine miscarriages.5
The terms spontaneous abortion, chemical pregnancy, and blighted ovum are ambiguous and should be avoided.
The use of consistent terminology and careful description of couples’ reproductive history is of the utmost importance in RPL research as it is a prerequisite for comparison of studies.
The GDG concludes to use the term RPL.
BMJ Best Practice10
Recurrent miscarriage is defined as two or more failed clinical pregnancies (i.e. documented by ultrasound or histopathology). It affects about 1% of all fertile couples trying to conceive in comparison with sporadic nonconsecutive miscarriages which occur in about 15–20% of all pregnancies. A miscarriage includes any pregnancy that ends before the age of viability which currently stands at 24 weeks’ gestation. A miscarriage that occurs before 12 weeks’ gestation is commonly termed an early or first trimester miscarriage, and one that occurs between 13 weeks and 24 weeks’ gestation is known as a late or second trimester miscarriage.
ASRM14
American Society for Reproductive Medicine defines RPL as two or more clinical pregnancy losses (documented by ultrasonography or histopathologic examination) but not necessarily consecutive.
ACOG—Up To Date2
The definition of RPL varies which makes studying the phenomenon and determining which couples to counsel or treat a more challenging event. As examples, varying definitions have been included:
- Two or more failed clinical pregnancies as documented by ultrasonography or histopathologic examination.
- Three consecutive pregnancy losses which are not required to be intrauterine.
The ACOG definition is clinically more relevant as most clinicians would start investigations for RPL after two consecutive losses.9 However, this would increase the prevalence of RPL to 5% as compared to previous 1% with three or more losses. It would also favorably skew the effect of treatment modalities. Hence it is thought that for research and publication purposes, we retain the definition of three or more losses. Logically, it will be hard to retain the RCOG definition, as changing trends in clinical practice will generate data accordingly. However, this heterogenecity in definition hinders scientific research and gives birth to varying clinical practices globally. Tulandi et al. have taken up all these considerations and suggested the following, which is 6acceptable in the present scenario of managing the women with pregnancy losses:5
- Two or more failed clinical pregnancies as documented by ultrasonography or histopathologic examination.
- Three consecutive pregnancy losses, which are not required to be intrauterine.
Recurrent implantation failure and preclinical pregnancy loss/very early pregnancy loss (VEPL) are markers of poor implantation and have a common spectrum with RPL.10 However the current definition does not take this into consideration. This is because both these entities are in themselves not clearly defined and hence data collection can be skewed. Preclinical losses with documented beta-hCG rise and fall are a clear indication of failed implantation and may result from genetically abnormal embryos. This is the reason why some authors believe that rather than the number of losses the time of take home a baby from the time of first pregnancy event should also be taken into consideration in the definition.
Recurrent implantation failure (RIF) is defined as no implantation after transfer of 10 Grade A embryos of day 2/3 maturity or 4 blastocyst of day 5 maturity, fresh and frozen cycles included. A standard definition is still lacking.10 This is an entity distinct from RPL although they both have many overlapping causes. They may be described as two ends of the same spectrum. Recurrent implantation failure is only relevant in the setting of assisted conception cycles whereas RPL is usually seen in spontaneous conceptions.
The incidence of acquired anatomical defects like uterine adhesions and cervical insufficiency may be higher in the secondary RPL group hence evaluation of the uterine cavity should always be done in this group.
It may also be proposed that in women greater than 37 years, one miscarriage should prompt genetic screening and replacement of a euploid embryo. Similarly, RIF, abnormal gamete morphology, poor quality embryos, and advanced maternal/paternal age should have sperm DNA fragmentation index (DFI) and preferably preimplantation genetic screening (PGS) of the trophectodermal cells and replacement of only euploid embryos prior to complete cessation of gametogenesis.
Women with a pregnancy loss will often ask “when is it best to try again?” Although the World Health Organization has recommended 6 months interpregnancy interval between pregnancies, there are studies to suggest that a shorter interpregnancy interval in women with RPL may have better outcomes.1
CONCLUSION
A thorough evaluation may be recommended after two consecutive pregnancy losses rather than three for better understanding and to ally apprehension and anxiety in the couple.7
With the advent of new diagnostic strategies like 23-chromosome microarray, there is a likelihood of revision in definitions and terminologies of RPL.
With newer diagnostic tools, we are likely to evolve into newer etiologies thereby reducing the prevalence of unexplained RPL.
REFERENCES
- World Health Organization. (2005). Report of WHO technical consultation on birth spacing. (online) Available from https://www.who.int/maternal_child_adolescent/documents/birth_spacing05/en/ [Last accessed November, 2019].
- Kutteh WH. Recurrent pregnancy loss. Precis: An Update in Obstetrics and Gynecology. Washington DC; American College of Obstetricians and Gynecologists; 2002. pp. 151–61.
- Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril. 1996;66(1):24–9.
- Royal College of Obstetricians and Gynaecologists. (2011). The Investigation and treatment of couples with recurrent miscarriages. Royal College of Obstetricians and Gynecologists green top guideline No. 17 May 2011. (online) Available from www.rcog.org.uk. [Last accessed November, 2019].
- Tulandi T, Eckler K. Definition and etiology of recurrent pregnancy loss. (online) Available from https://www.uptodate.com/contents/definition-and-etiology-of-recurrent-pregnancy-loss [Last accessed November, 2019].
- Bhattacharya S, Rajaram S, Gupta B, et al. Recurrent Miscarriage: Should the Definition be revised? Arora M, Bhattacharya S, Kumari V (Eds). World Clin Obstet Gynecol Recurrent Miscarriage. 2011;1(1).
- Kolte AM, Bernard LA, Christiansen OB, et al. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod. 2015;30(3):495–8.
- ESHRE Early Pregnancy Guideline Development Group. (2017). ESHRE guideline on recurrent pregnancy loss.
- Carson SA, Branch DW. Management of early recurrent pregnancy loss. ACOG Educ Bull. 2001;24:1–12.
- Arora M, Mukhopadhaya N. Recurrent pregnancy loss. Jaypee Brothers Medical Publishers (P) Ltd. 2018 Jun 30.
- Eastman NJ. Habitual abortion. In: Meigs JV, Sturgis SH, Taymor ML, Green TH (Eds). Progress in Gynecology, Volume 1. New York: Grune & Stratton; 1946.
- Branch DW, Silver RM. Antiphospholipid syndrome. ACOG Educ Bull. 1998;244:302–11.
- National Institute of Child Health and Human Development. (2012). What is pregnancy loss/miscarriage? (online) Available from https://www.nichd.nih.gov/health/topics/pregnancyloss/conditioninfo/causes [Last accessed November, 2019].
- Practice Committee of the American society for Reproductive Medicine. Evaluation and treatment of RPL: A committee opinion. Fertil Steril. 2002;98:1103–11.