Diagnosis and management of first trimester miscarriage
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f3676 (Published 19 June 2013) Cite this as: BMJ 2013;346:f3676
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Digital examination (pervaginum examination) can cause or aggravate the rupture of ectopic pregnancy. Then transvaginal ultrasonography (which is considered the best investigation in first trimester bleeding) may also prove to be as dangerous for ectopic pregnancy which is an important differential diagnosis of first trimester miscarriages.
Competing interests: No competing interests
Diagnosing miscarriage is often needed if 12 to 24% of women, with a missed menstrual period and positive urine pregnancy test, have miscarriages which are mostly caused by chromosomal abnormalities.1 It is also concerning that that the UK maternal mortality rates after miscarriage increased 4.4 times (from 0.05 to 0.22 per 100 000 maternities) from 1985 to 2008.2
This situation reflects lack of preconception care which is vitally important, especially when most women have been exposed to high doses of progesterone contraceptives from young ages which can disrupt cell chemistry including the balance of copper and zinc.3 An abortion rate of 31% was recorded in the 1974 RCGP OC study for women stopping the pill for side-effects but was 12% for never takers.4
In contrast, a 2002 to 2009 Foresight survey recorded a miscarriage rate of only 3% (4 in 1344 pregnancies) for couples completing a preconception care program. Most couples sought preconception care because of a history of “unexplained” infertility with previously failed IVF, ICSI or IUI attempts, and/or recurrent miscarriages. Both partners benefit from advice to avoid smoking, alcohol, hormonal or other medications, and to follow low allergy/high protein diets, for at least 3 months before conception. Also attempts were made to correct nutritional deficiencies and diagnose and treat genital infections before conception along with advice to use of non-hormonal contraception.
In my experience, the commonest findings over the past 40 years are deficiencies of zinc, magnesium, copper, selenium, B vitamins and PUFAs along with low superoxide dismutase (SOD) activities and sensitivities to toxic metals like nickel from stainless steel, cadmium from smoking and mercury from dental amalgams. These anomalies need to be corrected reduce the risk of miscarriage and fetal abnormalities. Miscarriage is likely if a low SOD activity is not treated, preferably before conception (with 1 mg copper in the morning and 30 mg zinc at night for 2 to 3 weeks followed by copper twice weekly and zinc every night). If the opportunity for preconception care has been missed, correcting low SOD activity in early pregnancy can prevent an otherwise inevitable miscarriage. Sperm abnormalities are very common with even small amounts of regular alcohol drinking but are usually correctable with avoidance and monitored nutritional supplements.
The US Center of Disease Control and Prevention (CDC) Surgeon General’s 2004 research report confirmed that women’s smoking during pregnancy increases the risk of pregnancy complications, premature delivery, low-birth-weight infants, stillbirth, and sudden infant death syndrome (SIDS). In 2001, 17.5% of teenaged mothers smoked during pregnancy. Only 18% to 25% of all women quit smoking once they become pregnant. Dr John McLaren-Howard reported at a Biolab Medical Unit meeting in 2004 that cadmium was the commonest DNA adduct in autistic children.6 I would doubt the validity of any “adjusted” epidemiological findings that smoking was not a cause of miscarriage or chromosomal abnormalities.
1 Jurkovic D, Overton C, Bender-Atik R. Diagnosis and management of first trimester miscarriage. BMJ2013;346:f3676.
2 Saving Mothers’ Lives. The eighth report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG2011;118(suppl 1):81-4.
3 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998;8:105-116.
4 The Royal College of General Practitioners. Oral Contraceptives and Health. Pitman Medical, London 1974.
5 Grant ECG. Prepregnancy or preconception care for both parents. BMJ, 9 June, 2012.
6 Grant ECG. McLaren-Howard J. Re: The effects of toxic metals in autistic children. BMJ 13 Sep 2004. http://bmj.com/cgi/eletters/329/7466/588-b#74117.
Competing interests: No competing interests
Jurkovic and colleagues present a clinical review on the diagnosis and management of first trimester miscarriage [1]. Making diagnoses is one of the major components of clinical decision making; however making diagnoses is susceptible to cognitive bias [2]. Critical to clinical decision making is keeping in mind alternative possibilities (differential diagnoses) which helps reduce making diagnostic and subsequently treatment errors, which can be catastrophic.
Clinical reviews of an entity should therefore routinely provide a list of key differential diagnoses to encourage clinicians not to lose sight of the bigger picture so as to minimize clinical errors. For example, here is an illustrative but not exhaustive list of entities that could present as a first trimester miscarriage [3,4]:
Ectopic pregnancy/Heterotopic pregnancy
Gestational trophoblastic disease
Cervix or vagina (infection, polyp, trauma, malignancy)
Uterus - fibroid
Ovarian cyst accident (torsion, rupture, hemorrhage)
Pelvic inflammatory disease
Implantation bleeding
Urinary tract – Cystitis
Gastrointestinal tract – Appendicitis
Hematologic - von Willebrand disease
References
1. Jurkovic D, Overton C, Bender-Atik R. Diagnosis and management of first trimester miscarriage. BMJ. 2013; 346:f3676.
2. Croskerry P. From Mindless to Mindful Practice — Cognitive Bias and Clinical Decision Making. N Engl J Med. 2013; 368(26):2445-8.
3. Deutchman M, Tubay AT, Turok D. First trimester bleeding. Am Fam Physician. 2009; 79(11):985-94.
4. Sebire NJ. The diagnosis of gestational trophoblastic disease in early pregnancy: implications for screening, counseling and management. Ultrasound Obstet Gynecol. 2005; 25(5):421-4.
Competing interests: No competing interests
I am very grateful to Dr Vaughan for her comments. There is little evidence to support the practice of performing vaginal examinations to diagnose ectopic pregnancy. Accuracy of vaginal examination to differentiate between intra- and extrauterine pregnancies is low and some authors have expressed concerns that it could potentially do harm by causing tubal rupture(1). Ruptured ectopic pregnancy should be suspected in all pregnant women presenting with severe abdominal pain or unusual gastro-intestinal symptoms. Abdominal palpation may also help to identify signs of peritonism caused by intra-abdominal bleeding. These women should be referred to the nearest casualty department without delay. It is true that some clinically stable women will also be diagnosed with ectopic pregnancies. In modern clinical practice; however, many unruptured ectopic pregnancies are managed conservatively and clinically stable women are best referred to their local early pregnancy units for ultrasound assessment and advice about the management.
The recent NICE guideline; however, provides ambiguous advice regarding the role of vaginal examination is suspected ectopic pregnancy(2). In the draft document vaginal examination was included in the initial assessment care pathway. After consultation reference to vaginal examination was removed form the final document, but the assessment of cervical motion tenderness was retained. During discussions at the meeting to mark launch of the guideline the majority of experts attending the meeting expressed opinion that vaginal examination should not be routinely performed in the assessment of women with suspected early pregnancy complications.
References
1.Mol BW, Hajenuis P, Engelsbel S, Ankum WM, van der Veen F, Henrika DJ, et al Should patients who are suspected of having an ectopic pregnancy undergo a physical examination? Fertil Steril 1999;71:155-7.
2.National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management in early pregnancy of ectopic pregnancy and miscarriage. CG154. 2012. http://publications.nice.org.uk/ectopic-pregnancy-and-miscarriage-cg154.
Competing interests: No competing interests
After having discussed in our Medical Staff the Clinical Review published in the BMJ by Davor Jurkovic, Caroline Overton and Ruth Bender-Atik. “Diagnosis and management of first trimester miscarriage” we would like to express our own experiences at our centre.
In a series of 295 patients with extremely severe maternal morbidity studied by us between 2008 and 2012 admitted to the intensive care unit (ICU) of our hospital, any patient had a complication secondary to abortion. The leading cause of admission to the ICU, by 23.4%, was Obstetric hemorrhage.
The highest percentages of spontaneous abortions that take place during the first quarter are the result of chromosomal abnormalities in the fertilized egg. Sometimes an abortion is the result of problems that occur during the delicate process of early development, it is often impossible to know with certainty what caused the miscarriage.
Obstetric hemorrhage or bleeding during pregnancy is a cause of maternal morbidity, perinatal and maternal mortality. Bleeding generally occur at different times in the course of pregnancy, in the article referred to occurred from early in pregnancy, often have identifiable risk conditions, recurring medical conditions, and over time, have accumulated evidence that has allowed the development of guidelines or protocols for handling.
Spontaneous abortions are less likely when you receive timely prenatal care.
References
1. Jurkovic D, Overton C, Bender-Atik R. Diagnosis and management of first trimester miscarriage. BMJ 2013;346:f3676
2. UNICEF. La morbilidad materna extremadamente grave, un reto actual para la reducción de la mortalidad materna. Madrid: Molinos Trade S.A. 2012: 61-89.
3. Cuba. Ministerio de Salud Pública. Consenso de procederes diagnósticos y terapéuticos en Obstetricia y Perinatología. La Habana: Ministerio de Salud pública; 2010.
Competing interests: No competing interests
I read with interest Jurkovic et al's statement that pelvic examination is unhelpful in the management of suspected miscarriage in early pregnancy (1). While I quite agree it is no substitute for ultrasound, I have always used it for the purpose of looking for signs of ectopic pregnancy. This is important in a general practice setting as open-access early pregnancy assessment units operate only between limited hours and, inevitably, a large proportion of women with bleeding in early pregnancy will have to wait until the next day for ultrasound assessment unless clinical assessment in primary care suggests that they need same-day referral.
Am I right in thinking that pelvic examination retains a place in triaging women who present to primary care with bleeding in early pregnancy, in order to select those who may not be able to safely wait for next day assessment? I have no desire to be performing genuinely unnecessary examinations, and would welcome the thoughts of the authors or others on this point.
(1) Jurkovic et al. Diagnosis and management of first trimester miscarriage. BMJ 2013;346:f3676 (22nd June)
Competing interests: No competing interests
Re: Diagnosis and management of first trimester miscarriage
Jurkovic et al (1) recently discuss thrombophilia as a cause of first trimester miscarriage in their review on the diagnosis and management of first trimester miscarriage.
The term ‘thrombophilia’ describes the presence of an acquired (including presence of persistent antiphospholipid antibodies, aPL) or inherited (antithrombin, protein C and protein S deficiency, prothrombin G20210A and factor V Leiden mutations, dysfibrinogenaemia) tendency to develop venous thrombotic events, while recurrent miscarriage is defined as a history of three previous miscarriages. The association of inherited thrombophilia with recurrent first trimester pregnancy loss has never been firmly established and often the subject of much debate, particularly with regards to whether the use of aspirin and anticoagulants are useful in preventing further miscarriage in this setting (2, 3, 4).
Persistent aPL have been established as a cause of recurrent miscarriage and are present in up to 20% of women who have recurrent miscarriage (5). Several plausible pathogenic mechanisms for the role of antiphospholipid antibodies in recurrent early miscarriage exist. Data from in vitro studies suggest APL have a direct effect on the trophoblast and decrease trophoblast invasiveness (6-8) and studies of animal models of APS demonstrate complement activation caused increased foetal loss (9-11) while complement inhibition protected from foetal injury (11). There are no such pathogenic mechanisms to explain how inherited thrombophilia might be responsible for recurrent early pregnancy loss (3).
Some reviews have suggested some of the inherited thrombophilias (Factor V Leiden and prothrombin G202010A mutations, antithrombin and protein C and S deficiency) may be a risk factor for recurrent early pregnancy loss (12,13,14,3), while others discuss the lack of evidence for an association between inherited thrombophilia and recurrent pregnancy loss (15). Studies were often small, usually retrospective and resulting data inconsistent.
Initial data on the use of aspirin and/or low molecular weight heparin suggested improved pregnancy outcomes in women with inherited thrombophilia and recurrent miscarriage (16, 17). Recent randomized controlled trials however have confirmed no benefit regardless of the presence of inherited thrombophilia (18, 19), although these studies included only small subgroups of patients with inherited thrombophilia. While current guidelines recommend the use of aspirin and heparin in women with aPL and recurrent miscarriage (4,20) – their use in women with inherited thrombophilia is not currently recommended since there is insufficient evidence their use improves pregnancy outcomes until further studies are conducted.
References
1. Jurkovic D, Overton C, Bender-Atik R. Diagnosis and management of first trimester miscarriage. BMJ. 2013;346:f3676.
2. Middeldorp S. Thrombosis in women: what are the knowledge gaps in 2013? J Thromb Haemost. 2013;11 Suppl 1:180-91.
3. Middeldorp S. Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost. 2007;5 Suppl 1:276-82.
4. Gyanecologists RCoOa. The Use of Antithrombotics in the Prevention of Recurrent Pregnancy Loss. 2011.
5. Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I, et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod. 1995;10:2001-5.
6. Di Simone N, Meroni PL, de Papa N, Raschi E, Caliandro D, De Carolis CS, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum. 2000;43:140-50.
7. Sebire NJ, Fox H, Backos M, Rai R, Paterson C, Regan L. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum Reprod. 2002;17:1067-71.
8. Quenby S, Mountfield S, Cartwright JE, Whitley GS, Chamley L, Vince G. Antiphospholipid antibodies prevent extravillous trophoblast differentiation. Fertil Steril. 2005;83:691-8.
9. Holers VM, Girardi G, Mo L, Guthridge JM, Molina H, Pierangeli SS, et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med. 2002;195:211-20.
10. Salmon JE, Girardi G. Antiphospholipid antibodies and pregnancy loss: a disorder of inflammation. J Reprod Immunol. 2008;77:51-6.
11. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004;10:1222-6.
12. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361:901-8.
13. Greer IA. Thrombophilia: implications for pregnancy outcome. Thromb Res. 2003;109:73-81.
14. Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132:171-96.
15. Rodger MA, Paidas M, McLintock C, Middeldorp S, Kahn S, Martinelli I, et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112:320-4.
16. Brenner B. Maternal anticoagulant prophylaxis for prevention of pregnancy loss in women with thrombophilia. J Thromb Haemost. 2003;1:416-7.
17. Gris JC, Mares P. The long and winding road ... towards LMWH for pregnancy loss. J Thromb Haemost. 2005;3:224-6.
18. Clark P, Walker ID, Langhorne P, Crichton L, Thomson A, Greaves M, et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115:4162-7.
19. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362:1586-96.
20. ACOG Practice Bulletin #68: Antiphospholipid syndrome. Obstet Gynecol. 2005;106:1113-21.
Competing interests: No competing interests