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Historically there has been a reluctance from researchers to enroll pregnant women in research trials, mostly due to fears of harm to the fetus [10]. Pregnant women are thus underrepresented in interventional studies, with efficacy and safety data often being extrapolated from analyses conducted in nonpregnant women. Cohort, registry and case‐control studies are the main sources of safety data of drugs in pregnancy, frequently relying on linkage methodology [7–10,15,16], while controlled interventional studies in pregnancy are often underpowered and focus mostly on labor and delivery rather than drug pharmacokinetics or teratogenicity [11,14,17]. In recent years, however, there has been an increasing number of scientists advocating a fair and representative inclusion of pregnant women in research [17,18].

In 1979, the FDA introduced a five‐letter risk classification to inform clinicians and women about a drug’s potential to cause congenital abnormalities if used in pregnancy (Table 7.1) [19]. This has recently been updated to a labeling system containing narrative summary information thought to be more patient‐friendly [20]. In the UK, the British National Formulary (BNF) simply categorizes drugs into those which may have harmful effects in pregnancy (indicating the potential abnormalities and trimester of risk) and those which are not known to be harmful in pregnancy [21].

The effects of drugs on pregnancy in general, and embryo development in particular, depend on a myriad of factors such as dose, duration of treatment, gestation of use, genetic susceptibility and placental clearance function [22]. In the first two weeks following fertilization, there is an “all‐or‐nothing” effect whereby drugs will either induce miscarriage or allow gestation to continue, although during this period certain exposures can still negatively affect surviving embryos [23]. The time of greatest teratogenic risk extends from the third to the eleventh week of pregnancy, when the basis of organogenesis is established [21]. Following the first trimester of gestation, adverse drug effects may result in growth restriction or disorders of the central nervous system and other organs, such as the kidneys and the heart [23].

The overall principles for prescribing drugs in women trying to conceive are as follows [21,24,25]:

1 Regularly reassess the need for medication in women trying to conceive or who become pregnant, and where possible consider nonpharmacological interventions.

2 Avoid drugs in the first trimester if possible.

3 Prescribe only if the expected benefit outweighs the risks.Table 7.1 FDA categories of risk for drugs in pregnancy [19].AAdequate and well‐controlled studies in animals and humans have failed to show fetal risk.BAnimal studies have failed to demonstrate a risk to the fetus, and there are no adequate and well‐controlled studies in pregnant women.CAnimal studies have shown an adverse effect on the fetus, and there are no adequate and well‐controlled studies in humans, although potential benefits may outweigh the risks.DEvidence of risk to the human fetus but benefits may still outweigh the risks.XEvidence of risk to the human fetus which clearly outweigh potential benefits—drug contraindicated in pregnancy.

4 Prescribe drugs that have long been used in pregnancy, with a good safety record, over new or untested drugs.

5 Use the smallest effective dose for the shortest period of necessity.

6 Consult a pharmacist or teratology information service when in doubt about a drug’s most up‐to‐date safety profile in pregnancy.

7 Always involve women in decisions made about pharmacological interventions in pregnancy.

A plethora of conditions are known to cause adverse pregnancy events. Chronic hypertension, for example, is linked to an increased risk of preeclampsia, fetal growth restriction and intrauterine fetal death [26]. Other diseases, such as diabetes mellitus and epilepsy, are known to increase the risk of congenital abnormalities if left untreated [27,28]. It may therefore be preferable to continue preconception medication or switch to drugs with a better safety profile in pregnant women with the aforementioned conditions and others, such as thyroid dysfunction, kidney disease or depression. In order to ensure patient safety, it is important that clinicians are adequately trained to identify teratogens and exercise the above principles when prescribing for women of reproductive age [25]. In addition, specialist input is frequently required in the management of women with chronic illnesses trying to conceive. For this reason, some hospitals offer multidisciplinary preconception clinics where maternal health clinicians and an extended multidisciplinary team of specialist physicians provide expert input in the management of complex medical conditions [29,30]. Women who conceive while on teratogens constitute an especially high‐risk group of patients and should have an early referral to a maternal‐fetal medicine specialist with multispecialty links, preferably in a tertiary referral center [31].

Table 7.2 provides examples of commonly prescribed drug classes and their safety profiles in pregnancy.

Table 7.2 Safety profile of different drug classes in pregnancy [6,21,24,25,32,33].

Drug class	Considered safe in pregnancy—use if necessary	Avoid in pregnancy if possible
Analgesics	Opioids (e.g. codeine, tramadol, pethidine, morphine, phentanyl) Paracetamol	COX‐2 inhibitors Gabapentin—supplement with high‐dose folate NSAIDs—avoid especially after 30 weeks of gestation Sumatriptan
Antibiotics	Amoxicillin + clavulanic acid Cephalosporins Clindamycin Erythromycin Flucloxacillin Gentamicin Metronidazole Nitrofurantoin (avoid in the third trimester) Penicillin Trimethoprim (avoid in the first trimester)	Azithromycin Co‐trimoxazole Doxycycline Imipenem Quinolones (e.g. ciprofloxacin and ofloxacin) Tetracycline
Anticoagulants	Low molecular weight heparin Unfractionated heparin	Warfarin New oral anticoagulants
Antidepressants	TCAs (e.g. amitriptyline, imipramine)	Lithium SNRIs (e.g. venlafaxine) SSRIs (e.g. fluoxetine, paroxetine, sertraline, citalopram)
Antidiabetics	Insulin Metformin	Sulfonylureas (e.g. gliclazide, glibenclamide)
Anticonvulsants	Carbamazepine Lamotrigine Levetiracetam	Phenytoin Phenobarbital Sodium valproate Topiramate
Antifungals	Clotrimazole (topical) Nystatin (topical)	Fluconazole Griseofulvin* Ketoconazole*
Antivirals	Aciclovir Nevirapine Zidovudine (AZT)	Amantadine* Ganciclovir* Ribavirin*
Biologics	Adalimumab (up to 28 weeks of gestation) Certolizumab (up to 32 weeks of gestation) Etanercept (up to 32 weeks of gestation) Infliximab (up to 22 weeks of gestation)	Belimumab Golimumab Rituximab
Cardiovascular drugs	Labetalol Methyldopa Nifedipine (modified release)	ACE inhibitors* (e.g. captopril, enalapril, ramipril) ARBs* (e.g. losartan, candesartan) Beta‐blockers
Cytotoxic drugs		Cyclophosphamide (stop 3 months before)* Methotrexate (absolutely contraindicated in pregnancy, stop 3 months before) Mycophenolate (stop 3 months before)
Endocrine drugs	Octreotide	Radioactive iodine Estradiol (unless indicated for luteal phase support) Progestogens (unless indicated for luteal phase support)
Immunosuppressant drugs	Azathioprine Cyclosporine A Sulfasalazine Tacrolimus	Cyclophosphamide (stop 3 months before)* Leflunomide (stop 24 months before)*
Gastrointestinal drugs	Cyclizine Metoclopramide Omeprazole Ondansetron (avoid in the first trimester) Promethazine Ranitidine	Lansoprazole
Others		Bisphosphonates* Fibrates* Misoprostol* Statins* Tamoxifen* Thalidomide* Live vaccines (e.g. Rubella, MMR)*

ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; COX, cyclo‐oxygenase; MMR, measles, mumps and rubella; NSAIDs, nonsteroidal anti‐inflammatory drugs; SNRI, serotonin‐noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants

^* Absolutely contraindicated in pregnancy