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Puzzlers

1. About 1% to 2% of pregnancies are ectopic. This is a serious complication. If a woman becomes pregnant with an IUD in place, the risk that the pregnancy is ectopic is considerably higher—the package insert for one brand of IUD (Mirena) says up to 50%. Does this mean that IUDs increase the risk of ectopic pregnancies? What would be an alternative interpretation?  

How could you resolve these alternative possibilities?

While the exact biological mechanism by which IUDs prevent conception is not fully understood, IUDs appear to be more effective at preventing a pregnancy from occurring within the uterus than outside the uterus. This effective prevention of in utero pregnancies produces an apparent excess of ectopic pregnancies among the pregnancies occurring with IUDs.

Whether the higher rate of ectopic pregnancies might also represent an absolute increase in risk of ectopic pregnancy is harder to determine. The ideal comparison would be with the same woman not using an IUD. Various case-control studies have attempted to include as control groups women who are at risk of pregnancy and not using IUDs. While these studies are imperfect, most show a net decrease in the occurrence of ectopic pregnancy in the presence of an IUD1—along with a decrease in the occurrence of intrauterine pregnancies.

2. A report from rural China found that perinatal mortality was three times higher for second births than for first births.2 Usually perinatal mortality declines with second parity (see Fig 5-8). What conditions in China might lead to this high mortality for second babies?

In a setting (such as China) where most women plan to have only one child, the most likely reason for having a second pregnancy is the failure of the first (fetal or infant death). Under these conditions, almost all women continuing to a second pregnancy are women who have demonstrated their high risk for perinatal problems—thus producing an elevated rate of perinatal mortality at second births.  

3. Among couples who seek infertility treatment, suppose that you identify a group in which the male partners are azospermic (without sperm), and another group in which the male partners are severely oligospermic (with very few sperm). If you were to compare the female partners of these two groups of men, would you expect them to have the same fertility?

If not, which women would you expect to be more fertile?

Let’s assume for the moment that the man’s sterility is not related to an infectious disease or other condition that the woman might share. Women whose husbands are absolutely sterile are likely to be unselected with regard to their own fertility. That is, women whose husbands are completely sterile are likely to have the same average fertility as the rest of the population. In contrast, women whose husbands are subfertile still have a small chance of conceiving. Among these women, the ones most likely to conceive are the highly fertile women—leaving behind the less fertile women who were not able to overcome the handicap of their husband’s subfertility. Thus, among infertile couples, women with subfertile husbands are more likely themselves to have lower fertility. This result was nicely demonstrated with real data by a group of French researchers.3 Clinical workups of infertile couples that stop when one cause of reduced fertility is found in one partner may miss important problems in the other partner.

4. Suppose you are planning to conduct a prospective study of pregnancy, and you want to include fecundability as one of your study endpoints. You could set eligibility in various ways. One, you could include all couples who are trying to conceive, regardless of how long they have been trying. Alternatively, you could restrict to couples who had just stopped their use of birth control to try to become pregnant. The advantage of the first is that you would find many more eligible couples. What would be the advantage of the second?

If you include couples who have already been trying, what essential additional information would you need?

It is tempting to recruit from the large pool of couples who are trying to conceive, but a problem is that these couples are less fertile than average. The most fertile couples conceive at the first or second cycle of trying, and they are therefore under-represented among couples who have been trying for 6 or 8 months. If you include all couples who are trying to conceive, you will enroll more couples more quickly, but you will also have to follow them for much longer in order to achieve the target number of pregnancies.

If you recruit couples who are already trying, it is essential to know how long they have already been trying, so that you can correctly determine their total time to pregnancy.

5. Intercourse during pregnancy may stimulate labor. While this hypothesis has some plausibility (there are abundant prostaglandins in semen, and prostaglandins play a role in the onset of labor), a randomized clinical trial has failed to show any effect of intercourse in triggering labor. 4

 An epidemiologic study reported a strong association between intercourse and reduced risk of preterm delivery.5 What might explain this association?

Reverse causation is a likely culprit in the association of intercourse with reduced risk of preterm. Women who are having signs of preterm labor may be advised by their doctors to avoid intercourse. More generally, women who are feeling healthy in their last trimester may be the ones most likely to continue to have intercourse during pregnancy.  

6. A Swedish study reported that women who took folic acid supplements were more likely to produce dizygotic twins.6 If the use of folic acid were to increase the chances of twinning, the higher mortality and complications among twins could outweigh the benefits of folic acid for the prevention of neural tube defects. This could argue against fortification of food with folic acid. The authors controlled for maternal age. Is there another possible confounding factor that you can think of?

One potential confounder is the presence of pregnancies conceived through ART. Such mothers are more likely to use vitamin supplements, and they are also much more likely to have dizygotic twins. The original paper considered the possibility of confounding by ART, but there was incomplete information for adjustment. A later study showed that that uncontrolled confounding by ART probably explained the whole association.7

7. Birth defects account for 17% of infant mortality in the US, but only 8% world-wide. Under-registration in developing countries no doubt contributes to this. Is there another contributing factor?

Other causes of death (such as infections) are much lower in the US. Thus, even though babies with birth defects may have better survival in the US, birth defects are a more common cause of infant death in the US than worldwide because other causes of infant death are less common.


  1. Mol BW, Ankum WM, Bossuyt PM, Van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52(6):337–41.

  2. Wu Z, Viisainen K, Wang Y, Hemminki E. Perinatal mortality in rural China: retrospective cohort study. BMJ 2003;327(7427):1319.

  3. Emperaire JC, Gauzere-Soumireu E, Audebert AJ. Female fertility and donor insemination. Fertil Steril 1982;37(1):90–3.

  4. Tan PC, Yow CM, Omar SZ. Effect of coital activity on onset of labor in women scheduled for labor induction: a randomized controlled trial. Obstet Gynecol 2007;110(4):820–6.

  5. Sayle AE, Savitz DA, Thorp JM, Jr., Hertz-Picciotto I, Wilcox AJ. Sexual activity during late pregnancy and risk of preterm delivery. Obstet Gynecol 2001;97(2):283–9.

  6. Ericson A, Kallen B, Aberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001;4(2):63–6.

  7. Berry RJ, Kihlberg R, Devine O. Impact of misclassification of in vitro fertilisation in studies of folic acid and twinning: modelling using population based Swedish vital records. BMJ 2005;330(7495):815.


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