Join Us | Latest Articles | Contact

Journal Home


Editorial Board


Recent Articles


Submit to this journal


Special Issues


Current issue

Obstetrics and Gynaecology Cases - Reviews





DOI: 10.23937/2377-9004/1410066



Familial Hypercholesterolemia and Pregnancy: Risk and Management

Roberta Mombelli1 and Giuliana Mombelli2*


1Clinic of Gynecology and Obstetrics in San Donato Hospital, Milan, Italy
2Dyslipidemia Center, Cardiotoracovascular Department, Niguarda Hospital, Milan, Italy


*Corresponding author: Giuliana Mombelli, Dyslipidemia Center, Cardiotoracovascular Department, Niguarda Hospital, Milan, Italy, E-mail: giuliana.mombelli@ospedaleniguarda.it
Obstet Gynecol Cases Rev, OGCR-2-066, (Volume 2, Issue 6), Review Article; ISSN: 2377-9004
Received: September 15, 2015 | Accepted: November 16, 2015 | Published: November 18, 2015
Citation: Mombelli R, Mombelli G (2015) Familial Hypercholesterolemia and Pregnancy: Risk and Management. Obstet Gynecol Cases Rev 2:066. 10.23937/2377-9004/1410066
Copyright: © 2015 Mombelli R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Abstract

Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth with elevated levels of low-density lipoprotein (LDL) cholesterol and increased risk for premature coronary heart disease (CHD) with clinical manifestation between the first and the fourth decades of life. Although statins are the most effective therapy for individuals with FH the use of statins is contraindicated during pregnancy. For this reason, before of a pregnancy the lipid-lowering drugs are discontinued because of possible teratogenic effects with modifications in estrogen and progesterone levels that negatively influence the lipid metabolism. Pregnancy in women affected by FH is rare and might be a critical challenge for both mother and fetus. There are limited therapeutic options available to treat pregnant women with FH and the potential risks to mother and fetus related to elevated cholesterol levels are a certainty. Regarding how to treat these women during pregnancy remains a challenge.


Key words

Familial hypercholesrolemia, Pregnancy risk, Treatment


Introduction

Familial hypercholesterolemia (FH) is an autosomal dominant disease, present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease (CHD). Currently three genes are known that can result in the phenotype of FH when affected by a mutation: the LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexintype9 (PCSK9). Historically, the clinical frequency of Homozygous FH (HoFH) has been estimated 1; 1,000,000. Heterozygous FH (HeFH) occurs in 1:500 individuals worldwide [1]. However, recent studies in unselected general populations suggest that the prevalence of HeFH based on the Dutch Lipid Clinic Network criteria may be as high as 1 in × 200 [2] or for molecularly defined HeFH, 1 in 244 [3]. Consequently, HoFH may affect as many as 1 in 160,000-300,000 people 2,3]. Heterozygous form is more frequent 1:85 in Christian Lebanese and in South African populations (1:67) [4]. Consequently in these countries HoFH are 1:28,800 in the first case and 1:18,000 in the second case [4]. Since birth, there are in both forms, very high levels of total cholesterol and LDL cholesterol (LDL-C) [5]. FH patients have a continuous exposition to cardiovascular disease (CVD) linked to elevated LDL-C levels. Subjects with FH have an increased risk to develop premature CVD approximately 20-fold increase respect to non-FH population if they not receive the lipid-lowering therapy [6-8]. Untreated women have a risk of 30% for a fatal or non-fatal coronary event by age 60 years. HoFH individuals have severe CVD before their 20 years. There is a very high incidence of mortality, coronary bypass surgery and severe aortic stenosis in young age. Diagnosis of FH can be made by clinical or genetic criteria [2]. There are elevated probabilities to find tendon xanthomas at any age (the most common in Achilles tendon and finger extensor tendons) or arcus corneae in patients under age 45.


Physiological modification and potential risk during pregnancy

Total cholesterol (TC) and triglycerides levels increase during gestation. Proposed biological explanations for these changes include a metabolic shift from carbohydrates to lipids for maternal energy production in order to make glucose available for the fetus [9] and an increase of cholesterol as a precursor for the production of steroid hormones in the placenta [10]. During pregnancy, physiological changes occur in lipids and lipoproteins, secondary to hormonal modifications: LDL-C increases to 42% at 36 weeks. In the second and third trimester, high-density-lipoprotein cholesterol (HDL-C) shows a 55% increase. Triglycerides increase from the third month until 36th week; they may raise even three-fold, achieving rapidly normal values after delivery, while cholesterol levels remain elevated for approximately 6 weeks after birth. It has been also observed an increase in Lipoprotein (a) [11-14] and PCSK9. Peticca et al. [15] have seen an elevated value of PCSK9 in pregnant women versus control cohorts (493,1 respect to 289,7 ng/ml, p < 0,001) whereas the newborn cohort was significantly lower than maternal level [15]. Napoli et al. [16] in FELIC study have reported that hyperlipidaemia may induce acute atherosclerosis in the utero-placental spiral arteries that, together with hypercoagulation, may result in local thrombosis and placental infarctions, leading to placental insufficiency and subsequent fetal compromise [16,17]. Some studies show that maternal hypercholesterolemia, independently of the FH status leads at formation atherosclerotic lesions in a larger extent in offspring compared to offspring of the mothers with normal cholesterol [5,16,18]. Furthermore, FH women develop aprothrombotic and proinflammatory phenotype, during pregnancy due to increased concentrations of several prothrombotic and inflammatory mediators compared to non-FHwomen [17,19]. In a previous study on over 2000 individuals it has been proved that FH patients born from a mother with FH have slightly but statistically significant higher LDL-C levels than those who inherited FH from their father [20], which suggests that patients who inherit FH through their mother may present, a more atherogenic lipid profile. In ABCD study has been reported a positive association of adverse pregnancy outcomes with high TC and triglycerides levels in the last term of pregnancy. Toleikyte et al. [21] have observed that FH women do not appear to have a higher risk of preterm delivery or of having infants with low birth weight or congenital malformations respect to women in general [21]. The atherogenic lipid profile with higher levels of TC, LDL-C and triglycerides that develops during pregnancy in women with FH, determines an increase of their CV risk [22]. The Framingham Heart study, an extensive population cohort study investigating risk factors for CV events, showed an elevated risk for CVD in women who had more than six pregnancies when compared with nulliparous women (relative risk 1.6; 95% confidence interval: 1.1-2.2) [23]. Versmissen et al. [24] have reported that the risk of CHD in untreated individuals with FH is more extreme when FH is transmitted maternally. Discontinuation of lipid-lowering medications for the relatively short duration of pregnancy is thought to have little impact on long-term therapy for primary hypercholesterolaemia [25] and is unlikely to affect outcomes of CHD. While, CV implications in HeFH women that for 5 years have not assumed statins for more pregnancies remain an unequivocal certainty.


Treatment and management of familial hypercholesterolemia in pregnancy

Considering the crucial role of cholesterol in fetal development as a background, therapeutic interventions should be meticulously titrated to achieve physiological cholesterol levels. Treatment consists in modifications of lifestyle (appropriate nutrition and physical activity are recommended for women with FH in pregnant), as well as aggressive cholesterol reduction with pharmacologic therapy [26,27]. Data in humans with respect to lipid-lowering interventions in pregnant women are scarce. Currently, statins are the mainstay of the treatment of hypercholesterolemia, and it is therefore tempting to consider these drugs for treatment of hypercholesterolemia during pregnancy. However, statins have shown teratogenic effects in animal studies [28]. The cases in which statins are continued during the first trimester of pregnancy are not rare being frequent the unplanned pregnancy [29]. The Food and Drug Administration (FDA) classifies the statins as category X in pregnancy. The exposition to lipophilic statins during first trimester determines defects of the central nervous system and unilateral limb deficiencies [30]. Colesevelam or cholestyramine (bile acid sequestrant) is located in category B during pregnancy, although there are no controlled studies that have assessed the safety of this agent in humans. Ezetimibe and niacin as category C in pregnancy, which means "animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, in spite of potential benefits may warrant use of the drug in pregnant women despite potential risks." Because the data in humans are limited it would seem prudent to avoid using these drugs during pregnancy or lactation. Women of childbearing age should be counseled to stop taking these medications at least 1 month before of the contraceptive therapy [26,30,31]. Recently, the FDA [32,33] approved two new drugs for treatment of FH, lomitapide (Juxtapid™) capsules and mipomersen sodium (Kynamro®) injection. Both of these medications are indicated as an adjunct for the management of HoFH, along with lipid-lowering medications and or LDL apheresis. Lomitapide is contraindicated during pregnancy (classified category X) as there is a risk of embryo-fetal toxicity, so women of child bearing age should be counseled on effective methods of contraception. If vomiting or diarrhea occurs, hormone absorption from oral contraceptives may be incomplete, necessitating the use of additional contraceptive methods. Before beginning treatment with lomitapide, a negative pregnancy test must be documented. Women who are taking mipomersen should be counseled to notify their health care provider if they become pregnant. It should not be used during pregnancy unless absolutely necessary. It is not known whether lomitapide or mipomersen is excreted in breast milk; therefore, women who are lactating should be counseled about decision-making to either discontinue the medication or to stop breastfeeding [34,35]. Because there are no controlled data on mipomersen in pregnant women (classified category B), it should only be used during pregnancy if extremely necessary. Studies on reproduction and embryo fetal development performed in mice and rabbits revealed no evidence an impaired fertility. Women who become pregnant while taking this medication should contact their health care provider [34]. Recently PCSK9 inhibitors have emerged as an alternative new class of cholesterol-lowering drugs. Until now, the best property of PCSK9 studied is to bind the hepatocyte-derived LDLR leading to its intracellular degradation. Disrupting this [PCSK9≡LDLR] protein-protein interaction prevents LDLR degradation, thereby raising LDLR levels, lowers LDL-C [36,37], keeping a protection for the development of atherosclerosis [38].This could be a very important therapeutic target in pregnant women.Evolocumab (RepathaTM) representsthe first PCSK9 inhibitor approved in the world for treatment of high cholesterol. The safety or contraindication for evolocumab in pregnancy, have not yet been evaluated. Long-term studies will establish whether the beneficial effects of PCSK9 inhibition of LDL-C levels directly translate into safety and effectiveness in CVD risk reduction. Despite its apparent safety, there are concerns about the inhibition of PCSK9 because we still know little about its global physiological functions [39]. The European Atherosclerosis Society (EAS) has made HoFH-specific recommendations for target LDL-C levels of < 100 mg/dL (< 2.5 mmol/L) in adults or < 70 mg/dL (< 1.8 mmol/L) in adults with clinical CHD or diabetes [2,40].

Evidence-based guidelines for FH from the National Lipid Association (NLA) recommend that treatment goals should focus on reducing LDL-C levels by 50% from pretreatment levels if target LDL-C levels cannot be achieved [41]. For high-risk patients (including HoFH patients), the NLA suggests that non-HDL-C and LDL-C levels must under < 130 mg/dL (3.4 mmol/L) and < 100 mg/dL (2.5 mmol/L), respectively. Many clinical trials exclude the women in pregnancy, determining a reduction of percentage of young women who participate in studies used to evaluate CV outcomes [41,42]. Moreover, this guideline has reported that the women with FH should receive pre-pregnancy counseling and instructions to stop lipid-lowering therapy at least four weeks before discontinuing contraception and should not use these drugs during pregnancy and lactation. Use of other lipid lowering medications (i.e. colesevelam or cholestyramine) may be considered. Furthermore, LDL-apheresis during pregnancy can be considered if there is CVD [42].

The International FH Foundation recommends that all women of child-bearing age should receive pre-pregnancy counseling with appropriate advice given by the clinician on contraception, before starting a statin and this should be reinforced at annual review. Statins and other lipid systemically absorbed lipid-regulating drugs should be discontinued 3 months before planned conception, as well as during pregnancy and breastfeeding. Furthermore, the adolescent girls should receive a pre-pregnancy counseling [43,44]. The implication is that pregnant women are unable to weight the potential benefits against the risks of treatment. Pregnant women traditionally have not participated in early stage clinical trials, creating significant safety concerns for treatment [45].


Summary

The management of FH becomes challenging in the women who have or wish to become pregnant because cholesterol levels increase during pregnancy and statins are contraindicated (Category X) during pregnancy and lactation. Actually, it is acceptable to use during pregnancy cholestyramine and colesevelam, because these medications do not pass into the systemic circulation, and have not been shown to have any adverse effects. Lomitapide is contraindicated in pregnancy, mipomersen can be used if it is absolutely necessary. LDL-apheresis procedure remains an important treatment that it must be considered in a clinical condition compromised (presence of CAD) in both forms. The use of PCSK9 inhibitor is unknown in pregnancy. In conclusion, in the future it will be very important to do studies that focus on therapeutic strategies that can give safely lower cholesterol levels during pregnancy in these women. The testing and treatment of pregnant women is in another challenging problem, because of a reluctance to expose developing foetuses to investigational drugs.


References
  1. Soutar AK, Naoumova RP (2007) Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat clin pract Cardiovasc med 4: 214-225.

  2. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, et al. (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur heart J 34: 3478-3490a.

  3. Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, et al. (2015) Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur heart J 36: 560-565.

  4. Austin MA, Hutter CM, Zimmern RL, Humphries SE (2004) Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 160: 407-420.

  5. Amundsen AL, Khoury J, Iversen PO, Bergei C, Ose L, et al. (2006) Marked changes in plasma lipids and lipoproteins during pregnancy in women with familial hypercholesterolemia. Atherosclerosis 189: 451-457.

  6. Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34-47.

  7. Ose L (2004) Diagnostic clinical and therapeutic aspects of familial hypercholesterolemia in children. Semin in vasc med 4: 51-57.

  8. Marks D, Thorogood M, Neil HA, Humphries SE (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168: 1-14.

  9. Di Cianni G, Volpe L, Lencioni C, Miccoli R, Cuccuru I, et al. (2003) Prevalence and risk factors for gestational diabetes assessed by universal screening. Diabetes Res Clin Pract 62: 131-137.

  10. Saarelainen H, Laitinen T, Raitakari OT, Juonala M, Heiskanen N, et al. (2006) Pregnancy-related hyperlipidemia and endothelial function in healthy women. Circ J 70: 768-772.

  11. Hameed AB, Tummala PP, Goodwin TM, Nuno I, Wani OR, et al. (2000) Unstable angina during pregnancy in two patients with premature coronary atherosclerosis and aortic stenosis in association with familial hypercholesterolemia. Am J obstet gynecol 182: 1152-1155.

  12. Fahraeus L, Larsson-Cohn U, Wallentin L (1985) Plasma lipoproteins including high density lipoprotein subfractions during normal pregnancy. Obstet Gynecol, 66: 468-472.

  13. Potter JM, Nestel PJ (1979) The hyperlipidemia of pregnancy in normal and complicated pregnancies. Am J obstet Gynecol 133: 165-170.

  14. Sattar N, Clark P, Greer IA, Shepherd J, Packard CJ (2000) Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with pre-eclampsia. Atherosclerosis 148: 407-411.

  15. Peticca P, Raymond A, Gruslin A, Cousins M, Adetola E, et al. (2013) Human Serum PCSK9 Is Elevated at Parturition in Comparison to Nonpregnant Subjects While Serum PCSK9 from Umbilical Cord Blood is Lower Compared to Maternal Blood. ISRN endocrinol.

  16. Napoli C, Glass CK, Witztum JL, Deutsch R, D'Armiento FP, et al. (1999) Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 354: 1234-1241.

  17. De Wolf F, Brosens I, Renaer M (1980) Fetal growth retardation and the maternal arterial supply of the human placenta in the absence of sustained hypertension. Br J Obstet Gynaecol 87: 678-685.

  18. Napoli C, D'Armiento FP, Mancini FP, Postiglione A, Witztum JL, et al. (1997) Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 100: 2680-2690.

  19. Amundsen AL, Khoury J, Sandset PM, Seljeflot I, Ose L, et al. (2007) Altered hemostatic balance and endothelial activation in pregnant women with familial hypercholesterolemia. Thromb Res 120: 21-27.

  20. van der Graaf A VM, Gaudet D, et al (2009) The dyslipidemia of mothers with familial hypercholesterolemia deteriorates lipid levels in their adult offspring. Oral presentation at the International Atherosclerosis Society Conference, Boston.

  21. Toleikyte I, Retterstøl K, Leren TP, Iversen PO (2011) Pregnancy outcomes in familial hypercholesterolemia: a registry-based study. Circulation 124: 1606-1614.

  22. Martin U, Davies C, Hayavi S, Hartland A, Dunne F (1999) Is normal pregnancy atherogenic? Clin Sci 96: 421-425.

  23. Ness RB, Harris T, Cobb J, Flegal KM, Kelsey JL, et al (1993) Number of pregnancies and the subsequent risk of cardiovascular disease. N Engl J Med 328: 1528-1533.

  24. Versmissen J, Botden IP, Huijgen R, Oosterveer DM, Defesche JC, et al. (2011) Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality. Atherosclerosis 219: 690-693.

  25. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP (1996) Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol 10: 439-46.

  26. Robinson JG, Goldberg AC(2011) Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 5: S18-29.

  27. Raal FJ, Santos RD (2012) Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 223: 262-268.

  28. Dostal LA, Schardein JL, Anderson JA (1994) Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits. Teratology 50: 387-394.

  29. Ofori B, Rey E, Berard A (2007) Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol 64: 496-509.

  30. Edison RJ, Muenke M (2004) Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 350: 1579-1582.

  31. Avis HJ, Hutten BA, Twickler MT, Kastelein JJ, van der Post JA, et al. (2009) Pregnancy in women suffering from familial hypercholesterolemia: a harmful period for both mother and newborn? Curr Opin Lipidol 20: 484-490.

  32. U.S. Food and Drug Administration (FDA) (2012) FDA news release. FDA approves new orphan drug for rare cholesterol disorder. Silver Spring MARfwf.

  33. U.S. Food and Drug Administration (FDA). (2013) FDA news release. FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder.

  34. Genzyme Corp. (2013). Kynamro [package insert]. Cambridge MARfhwkcmKFK-Pp.

  35. Aegerion Pharmaceuticals. (2012) Prescribing information. Cambridge MARfwjcpPIp.

  36. Horton JD, Cohen JC, Hobbs HH (2009) PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 50 Suppl: S172-177.

  37. Seidah NG (2009) PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Targets 13: 19-28.

  38. Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, et al. (2012) Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 125: 894-901.

  39. Hall SS (2013) Genetics: a gene of rare effect. Nature 496: 152-155.

  40. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, et al. (2014) Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 35: 2146-2157.

  41. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, et al. (2014) National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J C Lipidol 8: 473-488.

  42. Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, National Lipid Association Expert Panel on Familial Hypercholesterolemia (2011) Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 5: S9-17.

  43. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, et al. (2014) Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. J Clin lipidol 8: 148-172.

  44. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, et al. (2015) Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Eur J Prev Cardiol 22: 849-854.

  45. Gorember H, White A(1991) Off the Pedestal and into the Arena: toward including women in experimental protocols. Rev Law Soc Change19: 205-246.

International Journal of Anesthetics and Anesthesiology (ISSN: 2377-4630)
International Journal of Blood Research and Disorders   (ISSN: 2469-5696)
International Journal of Brain Disorders and Treatment (ISSN: 2469-5866)
International Journal of Cancer and Clinical Research (ISSN: 2378-3419)
International Journal of Clinical Cardiology (ISSN: 2469-5696)
Journal of Clinical Gastroenterology and Treatment (ISSN: 2469-584X)
Clinical Medical Reviews and Case Reports (ISSN: 2378-3656)
Journal of Dermatology Research and Therapy (ISSN: 2469-5750)
International Journal of Diabetes and Clinical Research (ISSN: 2377-3634)
Journal of Family Medicine and Disease Prevention (ISSN: 2469-5793)
Journal of Genetics and Genome Research (ISSN: 2378-3648)
Journal of Geriatric Medicine and Gerontology (ISSN: 2469-5858)
International Journal of Immunology and Immunotherapy (ISSN: 2378-3672)
International Journal of Medical Nano Research (ISSN: 2378-3664)
International Journal of Neurology and Neurotherapy (ISSN: 2378-3001)
International Archives of Nursing and Health Care (ISSN: 2469-5823)
International Journal of Ophthalmology and Clinical Research (ISSN: 2378-346X)
International Journal of Oral and Dental Health (ISSN: 2469-5734)
International Journal of Pathology and Clinical Research (ISSN: 2469-5807)
International Journal of Pediatric Research (ISSN: 2469-5769)
International Journal of Respiratory and Pulmonary Medicine (ISSN: 2378-3516)
Journal of Rheumatic Diseases and Treatment (ISSN: 2469-5726)
International Journal of Sports and Exercise Medicine (ISSN: 2469-5718)
International Journal of Stem Cell Research & Therapy (ISSN: 2469-570X)
International Journal of Surgery Research and Practice (ISSN: 2378-3397)
Trauma Cases and Reviews (ISSN: 2469-5777)
International Archives of Urology and Complications (ISSN: 2469-5742)
International Journal of Virology and AIDS (ISSN: 2469-567X)
More Journals

Contact Us

ClinMed International Library | Science Resource Online LLC
3511 Silverside Road, Suite 105, Wilmington, DE 19810, USA
Email: contact@clinmedlib.org
 

Feedback

Get Email alerts
 
Creative Commons License
Open Access
by ClinMed International Library is licensed under a Creative Commons Attribution 4.0 International License based on a work at https://clinmedjournals.org/.
Copyright © 2017 ClinMed International Library. All Rights Reserved.