Volume 1 - 1/2020, Review, 04-07

Editorial, 03 | DOI: 10.53260/grem.201011

Editorial

Andrea Riccardo Genazzani

Biochemical Pregnancies: How Should They Be Interpreted?

DOI: doi.org/10.53260/grem.201012 | Citation

Howard J. A. Carp

  • Howard J. A. Carp Dept. Obstetrics & Gynecology, Sheba Medical Center, Tel Hashomer, Israel & Tel Aviv University, Israel.

Abstract

There is little information in the literature about biochemical pregnancies (BPs). However, BPs (pregnancies which regress prior to imaging with ultrasound) are a major problem in IVF and recurrent miscarriage clinics. The reported incidence of between 13-22% of pregnancies may be confounded as today’s sensitive pregnancy tests may detect endometrial, pituitary or phantom hCG. Additionally, a false positive result may be due to extaneous hCG administered in an ART cycle. Hence the author has suggested the presence of rising hCG levels at two consecutive tests as a definition, and that one raised hCG level should be described as isolated. The etiology remains unclear. Embryonic aneuploidy, thinned endometrium, sperm defects and defective angiogenesis have been suggested. Additionally, a number of BPs are early ectopic pregnancies which fail to develop further.
Future live birth rates of 59% have been reported after BPs; however, BPs may be recurrent. The author treats recurrent BPs as recurrent pregnancy loss. However, treatment to prevent further BPs is empiric, with no evidence in the literature. The author uses hCG supplementation to enhance implantation. The results show a non-significant improvement in the subsequent live birth rate. The author has used IVIg in patients with >5 BPs. Nine live births were achieved in 19 pregnancies (47%). However, the results may be confounded as the previous BPs may have been early ectopic pregnancies, and the subsequent pregnancy intra-uterine.
If a BP becomes persistent, and hCG levels fail to fall, methotrexate may be required as in early ectopic pregnancies.

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Definition

Biochemical pregnancy (BP) is often also known by other terms, including chemical pregnancy, non-visualized pregnancy or pregnancy of unknown location (PUL). The most common definition of a BP is a positive βhCG test with no pregnancy on ultrasound. The most recent nomenclature is that of the European Society of Human Reproduction and Embryology (ESHRE), published in 2015. 1 The classification is based on a number of previous definitions. If there is a decreasing βhCG level and no localization of the pregnancy on ultrasound, if performed, the pregnancy is known as a non-visualized pregnancy 2. If no ultrasound has been performed, the pregnancy loss has been called a “biochemical pregnancy” 3. If the pregnancy resolves spontaneously after expectant management, the pregnancy is known as a resolved PUL after expectant management 4. If medical management such as methotrexate (MTX) is used, the pregnancy loss is known as a treated pregnancy loss after medical management.

The problem with all of the above definitions is that if βhCG levels are closely monitored, as is common in in vitro fertilization (IVF) programs, low levels of βhCG will be picked up and interpreted as a BP. Hence, there have been more strict definitions in the past, including an initial level of  10-1000iu hCG and a subsequent rising level 5,6: Coulam et al. 7 used a definition of two or more raised values of hCG with no gestational sac 3 weeks after embryo transfer.

The use of the term PUL suggests that the pregnancy may be ectopic. We suggest an alternative nomenclature: isolated raised hCG level, and biochemical or non-visualized pregnancy if the hCG level rises, when no extraneous hCG is administered.

As isolated raised hCG levels may peak and rapidly fall, the lack of substantial delay in the onset of the next menstrual period distinguishes a BP from a clinical pregnancy. The different outcome of a BP compared with a clinical pregnancy has led the American Society of Reproductive Medicine (ASRM) to distinguish BPs from clinical pregnancies, and not to recognize BPs as miscarriages. However, the European Society of Human Reproduction and Embryology (ESHRE) does recognize BPs as pregnancy losses, similar to miscarriages, partly based on Kolte et al.’s 2 observation that each non-visualized pregnancy loss reduces the chance of a subsequent live birth by 10% (RR, 0.90, CI 0.83; 0.97), similar to the risk conferred by each additional clinical miscarriage.

Isolated raised hCG levels

hCG can be detected from 7 days after ovulation 8, and can be used clinically from 9 days after the LH surge. A positive hCG test after 12 days is usually taken as indicative of pregnancy. However, modern tests are so sensitive that phantom, endometrial or pituitary hCG can also be detected. A low positive hCG value does not invariably mean that trophoblastic hCG is present. The tests may be confounded. Some tests use animal antibodies raised to hCG. If the patient harbours anti-animal antibodies after exposure to the same animal used in the test, a false positive result may occur. Additionally, if hCG was used for ovulation induction, it may still be present after 12 days. van de Weijer et al. 9 showed low amounts of hCG as a contaminant in hMG, and Kol 10 showed hCG to be present in Corifollitrophin α. Intra- and interlaboratory variation may also lead to false positive results. These low levels of hCG are isolated raised hCGs, not biochemical pregnancies.

Incidence of biochemical pregnancies

Various authors have assessed the incidence of BPs. In fertile patients, incidences in the range of 13-22% have been reported 11-13. Isolated raised hCG levels were reported in 4% of Liu et al.’s series 14. In the infertile population the incidence has been reported to be 14%-18%, which is not higher than in the fertile population 15,16   However, a higher incidence has been reported in IVF patients (22-31%) when compared with the general infertile population 17-19, and a rate of 22.5% was reported in Tamhankar et al.’s 20 study, as opposed to 5% in women who conceived spontaneously.  Salumets et al., 15 who studied a series of 1242 frozen embryo transfer cycles, reported that increased maternal age at IVF/ICSI was the only parameter elevating the BP rate, rather than IVF itself.

Causes of biochemical pregnancies

The cause of BPs may be dependent on the embryo, the mother, or even, possibly, the father. However, there is no information on BPs and sperm abnormalities. There is only information on male factors and recurrent pregnancy loss or recurrent implantation failure.

Embryo causes

Delayed implantation may be a cause or result of pregnancy loss, as hCG may be insufficient to allow implantation. The hCG produced at the start of pregnancy is mainly the hyperglycosylated form (hCG-H) 21,22. hCG-H is autocrine in nature, produced by the cytotrophoblast.  hCG-H drives the invasiveness of the syncytiotrophoblast. In Sasak1et al’s 23 study  only 8 of 36 BPs produced > 40% hCG-H on the day of implantation. All (100%) normal term pregnancies produced hCG-H levels greater than 40% . Alternatively, if implantation is delayed, there may be a slow rise in hCG levels. This slow rise  may indicate abnormal embryonic development. Abnormal embryonic development may have occurred after implantation either due to genetic or other embryonic factors 24.

As recurrent implantation failures and recurrent miscarriage are known to have a high incidence of aneuploidy, it is thought that BPs may be  due to a genetic aberrations. However, genetic aberrations have never been shown in BPs.

Maternal causes

Endometrial thickness has been reported to impact on BPs. In Dickey et al.’s report 25, BPs were found in 21.9% (7 of 32) of pregnancies if the endometrial thickness was less than 9 mm on the day of hCG administration in women undergoing ovulation induction, but in none of 49 pregnancies where the endometrial lining was greater than 9 mm.  Hence, it is possible that a thin endometrium may not allow proper invasion by the trophoblast, leading to inappropriate placentation.  Additionally, hCG secretion by the invading trophoblast may be negatively modulated by endothelin-1 (ET-1), or PG F2α found in the endometrium 26. Oxidative stress can also enhance hCG levels, while not leading to necrosis and apoptosis of the trophoblastic epithelium 27.

Implications of biochemical pregnancies

There is no question that the occurrence of a BP is extremely psychologically distressing for both partners. They feel joy in achieving a pregnancy after prolonged infertility, only to have that happiness dashed by pregnancy loss. Hence, the stress associated with BPs has led to patients leaving IVF programs 28.

The occurrence of a BP is a positive predictor of future IVF pregnancies 6,29, but a negative predictor of pregnancy outcomes, as BPs are associated with higher recurrent BP and miscarriage rates 30. Each non-visualized pregnancy loss has been reported to confer a decreased risk of a subsequent live birth (RR, 0.90, CI 0.83; 0.97), equivalent to the RR conferred by each additional clinical miscarriage 2. In cases of exclusively recurrent biochemical pregnancies, the risk of ectopic pregnancy has been reported to be 27%31. However, between 6% and 20% of women with a sporadic BP have an ectopic pregnancy 32.

Management

BPs may be non-viable or present with persistent raised hCG levels. In some cases, treatment with MTX may be required in order to induce trophoblast regression. MTX acts by halting DNA synthesis. In ectopic pregnancy, MTX is associated with a 67-94% success rate. However, it should be borne in mind that hCG initially rises when the trophoblast regresses. A meaningful fall in hCG is only seen after 7 days. Side effects such as stomatitis, gastrointestinal distress, dizziness, neutropenia, reversible alopecia, abdominal pain and vaginal bleeding or spotting may also be seen.

There is currently insufficient information in the literature to allow the formulation of guidelines for the management of patients after recurrent BPs. Below are some suggestions based on the author’s experience; they are not evidence based. If there is one isolated BP, it is this author’s opinion that there is little need for active treatment.  In the case of two consecutive BPs, there is still little need for active treatment. However, the ESHRE regards two BPs as two pregnancy losses, and therefore can be assumed to support treatment to prevent recurrence. In cases with three or more BPs, the present author treats the patients as if there were three or more miscarriages. Our database contains the details of 40 patients with two or more BPs who did not receive active treatment in the index pregnancy. There were 21 subsequent live births (53%). Eight subsequent pregnancies terminated as missed miscarriages (20%). There were ten subsequent BPs and one ectopic pregnancy.

Specific medications (author's Experience)

There is little information on various drugs used to improve the live birth rate. As stated above, hCG‐H accounts for 90% of the total hCG in first two to three weeks of pregnancy when invasive trophoblast activity is highest 21,22. Hence, a luteal dose of hCG is often administered in IVF practice in order to enhance implantation. Theoretically, hCG-H may prevent pregnancy failure at the time of implantation. However, hCG-H is patented and not commercially available, therefore, generally, commercially available hCG can be used instead. hCG prevents further miscarriages in recurrent miscarriage 33. The author has used hCG supplementation in 28 patients with three or more BPs: 20 subsequent pregnancies  ended in live births (71%). However, the numbers are too small to determine whether this 71% live birth rate is significantly different to the 59% seen in the control group (10 live births in 17 pregnancies).

The author has used intravenous immunoglobulin in patients with five or more BPs.  Nine live births were achieved in 19 pregnancies (47%).

Conclusions

It is clear that much more data on BPs are needed. Databases need to be combined in order increase the number of patients available for assessment. One possible source of “big data” is the database of the Society for Assisted Reproductive Technology (SART). However, as the SART does not recognize BPs as pregnancies, it would be necessary to search the database for hCG levels.

In recurrent pregnancy loss, there is a concept that the endometrium loses its selectivity, and allows abnormal embryos to implant. These abnormal embryos are then lost as miscarriages 34.  In recurrent BPs the opposite may be true, that the endometrium does not allow normal embryos to implant, and that these are lost as biochemical pregnancies.

Declaration of interest:

the author has no vested interest or conflict of interest
in this manuscript. No honorarium or perks have been received.

References

  1. ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018:hoy004.
  2. Kolte AM, van Oppenraaij RH, Quenby S, et al; ESHRE Special Interest Group Early Pregnancy. Non-visualized pregnancy losses are prognostically important for unexplained recurrent miscarriage. Hum Reprod. 2014;29:931-7.
  3. Farquharson RG, Stephenson MD, Eds in Early pregnancy, 2010 New York Cambridge University Press.
  4. Barnhart K, van Mello NM, Bourne T,  et al.  Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome. Fertil Steril. 2011;95:857-66.
  5. Carp HJ, Toder V, Mashiach S, Rabinovici J. Effect of paternal leukocyte immunization on implantation after biochemical pregnancies and repeated failure of embryo transfer. Am J Reprod Immunol. 1994;31:112-5.
  6. De Neubourg D, Gerris J, Mangelschots K, Van Royen E, Vercruyssen M, Elseviers M. Single top quality embryo transfer as a model for prediction of early pregnancy outcome. Hum Reprod. 2004;19:1476-9.
  7. Coulam CB, Chapman C, Rinehart JS. What is a preclinical pregnancy loss? J Assist Reprod Genet. 1998; 15:184-7.
  8. Lopata A, Hay DL. The potential of early human embryos to form blastocysts, hatch from their zona and secrete HCG in culture. Hum Reprod. 1989;4 (8 Suppl):87-94.
  9. van de Weijer BH, Mulders JW, Bos ES, Verhaert PD, van den Hooven HW. Compositional analyses of a human menopausal gonadotrophin preparation extracted from urine (menotropin). Identification of some of its major impurities. Reprod Biomed Online. 2003;7:547-57.
  10. Kol S. False positive blood hCG test following Corifollitropin alfa injection. Hum Reprod. 2018;33:177.
  11. Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG. Estimates of human fertility and pregnancy loss. Fertil Steril. 1996; 65:503-9.
  12. Coulam CB, Chapman C, Rinehart JS. What is a preclinical pregnancy loss?            J Assist Reprod Genet. 1998; 15:184-7.
  13. Hakim RB, Gray RH, Zacur H. Infertility and early-pregnancy loss. Amer J Obstet Gynecol. 1995;172:1510-7.
  14. Liu HC, Jones HW Jr, Rosenwaks Z. The efficiency of human reproduction after in vitro fertilization and embryo transfer. Fertil Steril. 1988;49:649-53.
  15. Salumets A, Suikkari AM, Mäkinen S, Karro H, Roos A, Tuuri T. Frozen embryo transfers: implications of clinical and embryological factors on the pregnancy outcome. Hum Reprod. 2006; 21:2368-74.
  16. Zeadna A, Son WY, Moon JH, Dahan MH. A comparison of biochemical pregnancy rates between women who underwent IVF and fertile controls who conceived spontaneously. Hum Reprod. 2015; 30:783-8.
  17.  Liu HC, Jones GS, Jones HW Jr, Rosenwaks Z. Mechanisms and factors of early pregnancy wastage in in vitro fertilization-embryo transfer patients. Fertil Steril. 1988;50:95-101.
  18. Bjercke S, Tanbo T, Dale PO, Mørkrid L, Abyholm T. Human chorionic gonadotrophin concentrations in early pregnancy after in-vitro fertilization. Hum Reprod. 1999;14:1642-6.
  19. Hourvitz A, Lerner-Geva L, Elizur SE, et al. Role of embryo quality in predicting early pregnancy loss following assisted reproductive technology. Reprod Biomed Online. 2006;13:504-9.
  20. Tamhankar VA, Liu B, Yan J, Li TC. A Comparison of Pattern of Pregnancy Loss in Women with Infertility Undergoing IVF and Women with Unexplained Recurrent Miscarriages Who Conceive Spontaneously. Obstet Gynecol Int. 2015;2015:989454.
  21. Cole LA. hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J Reprod Immunol. 2009;82:112-8.
  22. Evans J. Hyperglycosylated hCG: a Unique Human Implantation and Invasion Factor. Am J Reprod Immunol. 2016;75:333-40.
  23. Sasaki Y, Ladner DG, Cole LA. Hyperglycosylated human chorionic gonadotropin and the source of pregnancy failures. Fertil Steril 2008;89:1781-6.
  24. Liu HC, Rosenwaks Z. Early pregnancy wastage in IVF (in vitro fertilization) patients. J In Vitro Fert Embryo Transf. 1991;8:65-72.
  25. Dickey RP, Olar TT, Taylor SN, Curole DN, Harrigill K. Relationship of biochemical pregnancy to pre-ovulatory endometrial thickness and pattern in patients undergoing ovulation induction. Hum Reprod. 1993; 8:327-30.
  26. Sunder S, Lenton EA. Endocrinology of the peri-implantation period. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14:789-800.
  27. Jauniauz E, Poston L, Burton GJ. Placental-related diseases of pregnancy: Involvement of oxidative stress and implications in human evolution. Hum. Reprod. Update. 2006;12:747-55.
  28. Pearson KR, Hauser R, Cramer DW, Missmer SA. Point of failure as a predictor of in vitro fertilization treatment discontinuation. Fertil Steril. 2009;91(4 Suppl):1483-5.
  29. Haas J, Lerner-Geva L, Yerushalmi GM, et al. Previous abortion is a positive predictor for ongoing pregnancy in the next cycle in women with repeated IVF failures. Reprod Biomed Online. 2012;25:339-44.
  30. Yang R, Yang S, Li R, et al. Biochemical pregnancy and spontaneous abortion in first IVF cycles are negative predictors for subsequent cycles: an over 10,000 cases cohort study. Arch Gynecol Obstet. 2015; 292:453-8.
  31. Christiansen OB. Biochemical pregnancies—shall they count in the recurrent miscarriage diagnosis? J Reprod Immunol. 2011;90:155.
  32. Kirk E, Bottomley C, Bourne T. Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location. Hum Reprod Update. 2014;20:250-61.
  33. Morley LC, Simpson N, Tang T. Human chorionic gonadotrophin (hCG) for preventing miscarriage. Cochrane Database Syst Rev. 2013:CD008611.
  34. Teklenburg G, Salker M, Heijnen C, Macklon NS, Brosens JJ. The molecular basis of recurrent pregnancy loss: impaired natural embryo selection. Mol Hum Reprod. 2010;16:886-95.

Keywords: , ,

Citation: Carp H., Biochemical Pregnancies: How Should They Be Interpreted?, GREM Gynecological and Reproductive Endocrinology & Metabolism (2020); Volume 1 - 1/2020:04-07 doi: 10.53260/grem.201012

Published: February 6, 2020