IUD with progestogen

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IUD with progestogen
Mirena IntraUterine System.jpg
Correctly inserted IUD
Background
Birth control type Intrauterine
First use 1990 (Mirena—currently available)
1976 (Progestasert—discontinued in 2001)
Failure rates (first year (Mirena))
Perfect use 0.2%[1]
Typical use 0.2%[1]
Usage
Duration effect 5 years (Mirena)
3 years (Skyla)
Reversibility 2–6 months
User reminders Check thread position monthly
Clinic review One month after insertion, then annually
Advantages and disadvantages
STD protection No
Periods Causes menstrual irregularity, periods are usually lighter or none at all (amenorrhea)
Weight Potential side effect
Benefits No need to remember to take any daily action
Risks Ovarian cysts (usually benign)
Transient risk PID, Rare risk of uterine perforation, other potential adverse effects

Intrauterine device (IUD) with progestogen is a hormonal intrauterine device classified as a long-acting reversible contraceptive method. It is one of the most effective forms of birth control.[2] In the United Kingdom (UK), the IUD with progestogen is referred to as an intrauterine system (IUS) or intrauterine contraceptive (IUC). This article will refer to these devices as the hormonal IUD to distinguish from IUD with copper. Mirena is one brand available in the United States and UK.

It is on the World Health Organization's List of Essential Medicines, the minimum medicines needed in a basic health‐care system.[3]

Medical uses

In addition to birth control, hormonal IUD are used for prevention and treatment of:

Advantages

  • Considered one of the most effective forms of reversible birth control[2]
  • Can be used while breastfeeding[9] (see also nursing mothers)
  • No preparations needed before sex,[10] though routine checking of the device strings by patient and physician is advised to ensure proper placement remains intact[11]
  • 90% of users who wish to become pregnant do so within 24 months of removal.[12]
  • May experience lighter periods (some women stop having periods completely, see also amenorrhea)[13]
  • Effective for up to three to five years (depending on the IUD)[14]

Disadvantages

  • Irregular periods and spotting between periods often occurs after insertion[13]
  • Mild to moderate discomfort experienced during insertion procedure, including cramping or backache
  • Other potential adverse effects and risks

Effectiveness

After insertion, Mirena is effective for up to five years, although some studies have shown that it may be effective through seven years.[15] Skyla is effective for 3 years.[16]

The hormonal IUD is a long-acting reversible contraceptive, and is considered one of the most effective forms of birth control. The first year failure rate for the hormonal IUD is 0.2% and the five year failure rate is 0.7%.[17] These rates are comparable to tubal sterilization, but unlike sterilization the effects of the hormonal IUD are reversible.

The hormonal IUD is considered to be more effective than other common forms of reversible contraception, such as the birth control pill, because it requires little action by the user after insertion.[2] The effectiveness of other forms of birth control is mitigated (decreased) by the users themselves. If medication regimens for contraception are not followed precisely, the method becomes less effective. IUDs require no daily, weekly, or monthly regimen, so their typical use failure rate is therefore the same as their perfect use failure rate.[2]

In women with bicornuate uterus and in need of contraception, two IUDs are generally applied (one in each horn) due to lack of evidence of efficacy with only one IUD.[18] Evidence is lacking regarding progestogen IUD usage for menorrhagia in bicornuate uterus, but a case report showed good effect with a single IUD for this purpose.[19]

Breastfeeding

Progestogen-only contraceptives such as an IUD are not believed to affect milk supply or infant growth.[20] However, a study in the Mirena application for FDA approval found a lower continuation of breastfeeding at 75 days in hormonal IUD users (44%) versus copper IUD users (79%).[21]

When using Mirena, about 0.1% of the maternal dose of levonorgestrel can be transferred via milk to the nursed infant.[22] A six-year study of breastfed infants whose mothers used a levonorgestrel-only method of birth control found the infants had increased risk of respiratory infections and eye infections, though a lower risk of neurological conditions, compared to infants whose mothers used a copper IUD.[23] No longer-term studies have been performed to assess the long-term effects on infants of levonorgestrel in breast milk.

There are conflicting recommendations about use of Mirena while breastfeeding. The U.S. FDA does not recommend any hormonal method, including Mirena, as a first choice of contraceptive for nursing mothers.[citation needed] The World Health Organization recommends against immediate postpartum insertion, citing increased expulsion rates. It also reports concerns about potential effects on the infant's liver and brain development in the first six weeks postpartum. However, it recommends offering Mirena as a contraceptive option beginning at six weeks postpartum even to nursing women.[24] Planned Parenthood offers Mirena as a contraceptive option for breastfeeding women beginning at four weeks postpartum.[25]

Contraindications

A hormonal IUD should not be used by women who:

  • Are, or think they may be, pregnant[9]
  • Have abnormal vaginal bleeding that has not been explained[9]
  • Have untreated cervical or uterine cancer[9]
  • Have, or may have, breast cancer[9]
  • Have abnormalities of the cervix or uterus[26]
  • Have had pelvic inflammatory disease within the past 3 months[9]
  • Have had an STI such as chlamydia or gonorrhea within the past 3 months[9]
  • Have liver disease or tumor[26]
  • Have an allergy to levonorgestrel or any of the inactive ingredients included in the device[26]

Insertion of an IUD is not recommended for women having had a D&E abortion (second-trimester abortion) within the past four weeks.[25] To reduce the risk of infection, insertion of an IUS is not recommended for women that have had a medical abortion but have not yet had an ultrasound to confirm that the abortion was complete, or that have not yet had their first menstruation following the medical abortion.[25]

A full list of contraindications can be found in the WHO Medical Eligibility Criteria for Contraceptive Use and the CDCUnited States Medical Eligibility Criteria for Contraceptive Use.[9][27]

Adverse effects

  • Irregular menstrual pattern: irregular bleeding and spotting is common in the first 3 to 6 months of use. After that time periods become shorter and lighter, and 20% of women stop having periods after 1 year of use.[28] The average user reports 16 days of bleeding or spotting in the first month of use, but this diminishes to about four days at 12 months.[29][30]
  • Cramping and Pain: many women feel discomfort or pain during and immediately after insertion. Some women may have cramping for the first 1–2 weeks after insertion.[31]
  • Expulsion: Sometimes the IUD can slip out of the uterus. This is termed expulsion. Around 5% of IUD users experience expulsion. If this happens a woman is not protected from pregnancy.[31][32] Expulsion is more common in younger women, women who have not had children, and when an IUD is inserted immediately after childbirth or abortion.[33][34][35]
  • Perforation: Very rarely, the IUD can be pushed through the wall of the uterus during insertion. Risk of perforation is mostly determined by the skill of the practitioner performing the insertion. For experienced medical practitioners, the risk of perforation is 1 per 1,000 insertions or less.[36] With postpartum insertions, perforation of the uterus is more likely to occur when uterine involution is incomplete; involution usually completes by 4–6 weeks postpartum.[34] Special considerations apply to women who plan to breastfeed. If perforation does occur it can damage the internal organs, and in some cases surgery is needed to remove the IUD.
  • Pregnancy complications: Although the risk of pregnancy with an IUD is very small, if one does occur there is an increased risk of serious problems. These include ectopic pregnancy, infection, miscarriage, and early labor and delivery. As many as half the pregnancies that occur in Mirena users may be ectopic. The incidence rate of ectopic pregnancies is approximately 1 per 1000 users per year.[37] Immediate removal the IUD is recommended in the case of pregnancy.[31][32] No pattern of birth defects was found in the 35 babies for whom birth outcomes were available at the time of FDA approval.[38]
  • Infection: The insertion of the IUD does have a small risk of pelvic inflammatory disease (PID). Concurrent infection with gonorrhea or chlamydia at the time of insertion increases the risk of pelvic inflammatory disease.[39] If PID does occur, it will most likely happen within 21 days of insertion. The device itself does not increase the risk of infection.[31]
  • Ovarian Cysts: Enlarged follicles (ovarian cysts) have been diagnosed in about 12% of the subjects using a hormonal IUD. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the enlarged follicles disappear spontaneously after two to three months. Surgical intervention is not usually required.[40]
  • Mental health changes including: nervousness, depressed mood, mood swings[26]
  • Weight gain[26]
  • Headache, migraine[26]
  • Nausea[26]
  • Acne[26]
  • Excessive hairiness[26]
  • Lower abdominal or back pain[26]
  • Decreased libido[26]
  • Itching, redness or swelling of the vagina[26]
  • Vaginal discharge[41]
  • Breast pain, tenderness[41]
  • Edema[41]
  • Abdominal distension[41]
  • Cervicitis [41]
  • May affect glucose tolerance [41]
  • May experience a change in vision or contact lens tolerance [12]
  • May deplete Vitamin B1 which can affect energy, mood, and nervous system functioning [12]
  • A "lost coil" occurs when the thread cannot be felt by a woman on routine checking and is not seen on speculum examination.[42] Various thread collector devices or simple forceps may then be used to try to grasp the device through the cervix.[43] In the rare cases when this is unsuccessful, an ultrasound scan may be arranged to check the position of the coil and exclude its perforation through into the abdominal cavity or its unrecognised previous expulsion.

Cancer

According to a 1999 evaluation of the studies performed on progestin-only birth control by the International Agency for Research on Cancer, there is some evidence that progestin-only birth control reduces the risk of endometrial cancer. The IARC concluded that there is no evidence progestin-only birth control increases the risk of any cancer, though the available studies were too small to be definitively conclusive.[44]

Bone density

No evidence has been identified to suggest Mirena affects bone mineral density (BMD).[45] Two small studies, limited to studying BMD in the forearm, show no decrease in BMD.[46][47] One of the studies showed at 7 years of use, similar BMD at the midshaft of the ulna and at the distal radius as nonusers matched by age and BMI.[46] In addition, BMD measurements were similar to the expected values for women in the same age group as the participants. The authors of the study said their results were predictable, since it is well established that the main factor responsible for bone loss in women is hypoestrogenism, and, in agreement with previous reports, they found estradiol levels in Mirena users to be normal.[46]

Composition and hormonal release

Mirena IUD visible on pelvic radiograph.

The hormonal IUD is a small 'T'-shaped piece of plastic, which contains levonorgestrel, a type of progestin.[17] The cylinder of the device is coated with a membrane that regulates the release of the drug.[48] Mirena releases the drug at an initial rate of 20 micrograms per day. This declines to a rate of 14 micrograms per day after 5 years, which is still in the range of clinical effectiveness. Skyla releases 14 micrograms per day and declines to 5 micrograms per day after 3 years.[16] Jaydess releases 6 micrograms per day and lasts for 3 years.[49] In comparison, oral contraceptives can contain 150 micrograms of levonorgestrel.[31] The hormonal IUD releases the levonorgestrel directly into the uterus, as such its effects are mostly paracrine rather than systemic. Most of the drug stays inside the uterus, and only a small amount is absorbed into the rest of the body.[31] Blood levels of levonorgestrel in Mirena users are half those found in Norplant users and one-tenth those found in users of levonorgestrel-only pills).[50]

Insertion and removal

Schematic depiction of vaginal ultrasonography of a Mirena.
Vaginal ultrasonography showing a Mirena in optimal place in the uterus, as viewed from angle shown in schematic depiction.

The hormonal IUD is inserted in a similar procedure to the nonhormonal copper IUD, and can only be inserted by a qualified medical practitioner.[31] Before insertion, a pelvic exam is performed to examine the shape and position of the uterus. It is also recommended that patients be tested for gonorrhea and chlamydia prior to insertion, as a current STI at the time of insertion can increase the risk of pelvic infection.[51] During the insertion, the vagina is held open with a speculum, the same device used during a pap smear.[31] A grasping instrument is used to steady the cervix, the length of the uterus is measured for proper insertion, and the IUD is placed using a narrow tube through the opening of the cervix into the uterus.[31] A short length of monofilament plastic/nylon string hangs down from the cervix into the vagina. The string allows physicians and patients to check to ensure the IUD is still in place and enables easy removal of the device.[31] Mild to moderate cramping can occur during the procedure, which generally takes five minutes or less. Insertion can be performed immediately postpartum and post-abortion if no infection has occurred.[9] Misoprostol is not effective in reducing pain in IUD insertion.[52]

Removal of the device should also be performed by a qualified medical practitioner. After removal, fertility will return to previous levels relatively quickly.[53] One study found that the majority of participants returned to fertility within three months.[54]

Mechanisms of action

The hormonal IUD's primary mechanism of action is to prevent fertilization.[31][55][56][57][58] The levonorgestrel intrauterine system has several contraceptive effects:

  • The inside of the uterus becomes fatal to sperm[57][59]
  • Cervical mucus thickens[15]
  • Ovulation is not inhibited[60]
  • They can also thin the endometrial lining and potentially impair implantation but this is not the usual function.[61][62]

Numerous studies have demonstrated that IUDs primarily prevent fertilization, not implantation.[31] In one experiment involving tubal flushing, fertilized eggs were found in half of women not using contraception, but no fertilized eggs were found in women using IUDs.[63] IUDs also decrease the risk of ectopic pregnancy, which further implies that IUDs prevent fertilization.[31]

History

Hormonal IUDs were developed in the 1990s following the development of the copper IUD in the 1960s and 1970s.[64] Dr. Antonio Scommenga, working at the Michael Reese Hospital in Chicago, discovered that administering progesterone inside the uterus could have contraceptive benefits.[64] With knowledge of Scommegna's work, a Finnish doctor, Jouni Valtteri Tapani Luukkainen, created the 'T'-shaped IUD that released progesterone, marketed as the Progestasert System. This IUD had a short, 1-year lifespan and never achieved widespread popularity. Following this relative lack of success, Dr. Luukkainen replaced the progesterone with the hormone levonorgestrel to be released over a 5-year period, creating what is now Mirena.[65]

The Mirena IUD was studied for safety and efficacy in two clinical trials in Finland and Sweden involving 1,169 women who were all between 18 and 35 years of age at the beginning of the trials. The trials included predominantly Caucasian women who had been previously pregnant with no history of ectopic pregnancy or pelvic inflammatory disease within the previous year. Over 70% of the participants had previously used IUDs.[66]

In 2013 Skyla, a lower dose levonorgestrel IUD effective for up to 3 years, was approved by the FDA.[67] Skyla has a different bleeding pattern than Mirena, with only 6% of women in clinical trials becoming amenorrheic (compared to approximately 20% with Mirena). In 2015, Liletta was approved by the FDA. Liletta has a similar size and levonorgestrel release characteristics as Mirena, and is FDA-approved for 3 years of use following a study in which 6 women out of 1,751 conceived while using Liletta.[68]

Controversies

In 2009, Bayer, the maker of Mirena, was issued an FDA Warning Letter by the United States Food and Drug Administration for overstating the efficacy, minimizing the risks of use, and making "false or misleading presentations" about the device.[69][70] From 2000 to 2013, the federal agency received over 70,072 complaints about the device and related adverse effects.[71][72] Activist Erin Brockovich has launched a website for women who have experienced adverse effects to share their experiences.[73][74] Over 1,000 lawsuits have been filed in the United States.[70][75]

References

  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'strict' not found. Table 26–1 = Table 3–2 Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception, and the percentage continuing use at the end of the first year. United States.
  2. ↑ 2.0 2.1 2.2 2.3 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 4.2 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 12.2 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.0 13.1 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ 15.0 15.1 Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ 16.0 16.1 Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ 17.0 17.1 [1], Bayer Pharmaceuticals.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ FDA Medical Review p. 37.
  22. ↑ MIRENA® Data Sheet, Bayer NZ, 11 December 2009http://www.bayerresources.com.au/resources/uploads/DataSheet/file9503.pdf Retrieved 2011-02-10
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found. pp.101, 113.
  25. ↑ 25.0 25.1 25.2 Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ 26.00 26.01 26.02 26.03 26.04 26.05 26.06 26.07 26.08 26.09 26.10 26.11 Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ 31.00 31.01 31.02 31.03 31.04 31.05 31.06 31.07 31.08 31.09 31.10 31.11 31.12 Lua error in package.lua at line 80: module 'strict' not found. p.150:

    Mechanism of action
    Although the precise mechanism of action is not known, currently available IUCs work primarily by preventing sperm from fertilizing ova.26 IUCs are not abortifacients: they do not interrupt an implanted pregnancy.27 Pregnancy is prevented by a combination of the "foreign body effect" of the plastic or metal frame and the specific action of the medication (copper or levonorgestrel) that is released. Exposure to a foreign body causes a sterile inflammatory reaction in the intrauterine environment that is toxic to sperm and ova and impairs implantation.28,29 The production of cytotoxic peptides and activation of enzymes lead to inhibition of sperm motility, reduced sperm capacitation and survival, and increased phagocytosis of sperm.30,31… The progestin in the LNg IUC enhances the contraceptive action of the device by thickening cervical mucus, suppressing the endometrium, and impairing sperm function. In addition, ovulation is often impaired as a result of systemic absorption of levonorgestrel.23
    p. 162:
    Table 7-1. Myths and misconceptions about IUCs
    Myth: IUCs are abortifacients. Fact: IUCs prevent fertilization and are true contraceptives.

  32. ↑ 32.0 32.1 Lua error in package.lua at line 80: module 'strict' not found.
  33. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  34. ↑ 34.0 34.1 Lua error in package.lua at line 80: module 'strict' not found.
  35. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  36. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  37. ↑ FDA Medical Review pp. 3-4
  38. ↑ FDA Medical Review p. 5,41
  39. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  40. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 Lua error in package.lua at line 80: module 'strict' not found.
  42. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  43. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  44. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  45. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  46. ↑ 46.0 46.1 46.2 Lua error in package.lua at line 80: module 'strict' not found.
  47. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  48. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  49. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  50. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  51. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  52. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  53. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  54. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  55. ↑ Lua error in package.lua at line 80: module 'strict' not found. p. S28:

    Conclusions
    Active substances released from the IUD or IUS, together with products derived from the inflammatory reaction present in the luminal fluids of the genital tract, are toxic for spermatozoa and oocytes, preventing the encounter of healthy gametes and the formation of viable embryos. The current data do not indicate that embryos are formed in IUD users at a rate comparable to that of nonusers. The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence. The bulk of the data indicate that interference with the reproductive process after fertilization has taken place is exceptional in the presence of a T-Cu or LNG-IUD and that the usual mechanism by which they prevent pregnancy in women is by preventing fertilization.

  56. ↑ Lua error in package.lua at line 80: module 'strict' not found. p. 199:

    Mechanisms of action
    Thus, both clinical and experimental evidence suggests that IUDs can prevent and disrupt implantation. It is unlikely, however, that this is the main IUD mode of action, … The best evidence indicates that in IUD users it is unusual for embryos to reach the uterus.
    In conclusion, IUDs may exert their contraceptive action at different levels. Potentially, they interfere with sperm function and transport within the uterus and tubes. It is difficult to determine whether fertilization of the oocyte is impaired by these compromised sperm. There is sufficient evidence to suggest that IUDs can prevent and disrupt implantation. The extent to which this interference contributes to its contraceptive action is unknown. The data are scanty and the political consequences of resolving this issue interfere with comprehensive research.
    p. 205:
    Summary
    IUDs that release copper or levonorgestrel are extremely effective contraceptives... Both copper IUDs and levonorgestrel releasing IUSs may interfere with implantation, although this may not be the primary mechanism of action. The devices also create barriers to sperm transport and fertilization, and sensitive assays detect hCG in less than 1% of cycles, indicating that significant prevention must occur before the stage of implantation.

  57. ↑ 57.0 57.1 Lua error in package.lua at line 80: module 'strict' not found. pp. 246–247:

    Mechanism of action
    The contraceptive action of all IUDs is mainly in the intrauterine cavity. Ovulation is not affected, and the IUD is not an abortifacient.58–60 It is currently believed that the mechanism of action for IUDs is the production of an intrauterine environment that is spermicidal.
    Nonmedicated IUDs depend for contraception on the general reaction of the uterus to a foreign body. It is believed that this reaction, a sterile inflammatory response, produces tissue injury of a minor degree but sufficient enough to be spermicidal. Very few, if any, sperm reach the ovum in the fallopian tube.
    The progestin-releasing IUD adds the endometrial action of the progestin to the foreign body reaction. The endometrium becomes decidualized with atrophy of the glands.65 The progestin IUD probably has two mechanisms of action: inhibition of implantation and inhibition of sperm capacitation, penetration, and survival.

  58. ↑ Lua error in package.lua at line 80: module 'strict' not found. p. 259:

    Intrauterine devices
    Mechanisms of action
    The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence... Because concern over mechanism of action represents a barrier to acceptance of this important and highly effective method for some women and some clinicians, it is important to point out that there is no evidence to suggest that the mechanism of action of IUDs is abortifacient.
    The LNG-IUS, like the copper device, has a very low ectopic pregnancy rate. Therefore, fertilization does not occur and its main mechanism of action is also preconceptual. Less inflammation occurs within the uterus of LNG-IUS users, but the potent progestin effect thickens cervical mucus to impede sperm penetration and access to the upper genital track. Although the LNG-IUS also produces a thin, inactive endometrium, there is no evidence to suggest that this will prevent implantation, and the device should not be used for emergency contraception.

  59. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  60. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  61. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  62. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  63. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  64. ↑ 64.0 64.1 Lua error in package.lua at line 80: module 'strict' not found.
  65. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  66. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  67. ↑ FDA drug approval for Skyla
  68. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  69. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  70. ↑ 70.0 70.1 Lua error in package.lua at line 80: module 'strict' not found.
  71. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  72. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  73. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  74. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  75. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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